Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology¶

Chapter 415 | Part 12: Endocrinology and Metabolism | Harrison's Principles of Internal Medicine, 22nd Edition

KEY CLINICAL POINTS¶

Diabetes mellitus (DM) is a group of metabolic disorders sharing the phenotype of hyperglycemia, with type 1 DM resulting from autoimmune beta cell destruction and type 2 DM from insulin resistance combined with inadequate insulin secretion
Diagnostic criteria: HbA1c ≥ 6.5%, FPG ≥ 7.0 mmol/L (126 mg/dL), 2-h PG ≥ 11.1 mmol/L (200 mg/dL), or random glucose ≥ 11.1 mmol/L with classic symptoms
Global prevalence has risen dramatically to 537 million adults (10.5%) in 2021, projected to reach 783 million by 2045, with type 2 DM representing >90% of cases
Type 1 DM is now staged based on autoantibody development (Stage 1), dysglycemia (Stage 2), and clinical diabetes (Stage 3), enabling earlier intervention with teplizumab
Prevention of type 2 DM through lifestyle modification (diet and exercise) can reduce progression by 58%, with metformin providing 31% reduction

1. DEFINITION & OVERVIEW¶

Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. Several distinct types of DM are caused by a complex interaction of genetics and environmental factors. Depending on the etiology, factors contributing to hyperglycemia include: - Reduced insulin secretion - Decreased glucose utilization - Increased glucose production The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems that impose a tremendous burden on individuals and health care systems.

1.1 Clinical Significance¶

In the United States, DM is the leading cause of: - End-stage renal disease (ESRD) - Nontraumatic lower-extremity amputations - Adult blindness Persons with diabetes are at increased risk for cardiovascular disease, which is the main cause of morbidity and mortality in this population.

2. EPIDEMIOLOGY¶

The worldwide prevalence of DM has risen dramatically over the past four decades, from an estimated 30 million cases in 1985 to 537 million in 2021 (prevalence of 10.5%). Based on current trends, the International Diabetes Federation (IDF) projects: - 643 million adults (20-79 years) by 2030 (prevalence 11.3%) - 783 million by 2045 (prevalence 12.2%) Approximately 75% of individuals with diabetes live in low- or middle-income countries. Globally, ~50% of those with diabetes in middle- and low-income countries are undiagnosed.

2.1 Geographic Distribution¶

Countries with the greatest number of individuals with diabetes (2021): - China: 140.9 million - India: 74.2 million - Pakistan: 33.0 million - United States: 32.2 million - Indonesia: 19.5 million - Brazil: 15.7 million - Mexico: 14.1 million

2.2 United States Prevalence¶

CDC estimates (2021): - 11.6% of the U.S. population has diabetes - 38% of U.S. adults have prediabetes - 22.8% of adults with diabetes are undiagnosed Age-adjusted prevalence by ethnicity (2019-2021): - Non-Hispanic whites: 10.3% - Asians: 9.2% - Hispanics: 10.3% - Non-Hispanic blacks: 12.5% - Native American/Alaskan native: 16%

U.S. prevalence by age group: - 18-44 years: 3.0% - 45-64 years: 14.5% - >65 years: 24.4%

2.4 Type 1 DM Geographic Variation¶

Highest incidence: Scandinavia and Middle East
Lowest incidence: Pacific Rim
Intermediate: Northern Europe and United States Countries with greatest number of type 1 DM (onset <19 years): India, United States, Brazil, China

2.5 Mortality and Economic Impact¶

Diabetes was the eighth leading cause of death in the United States (2021)
IDF estimated 6.7 million diabetes-related deaths worldwide (2021)
Accounts for 12.2% of global all-cause mortality in adults 20-79 years
~1/3 of diabetes-related deaths occur in individuals <60 years
~$1 trillion in global healthcare expenditures (2021)

3. CLASSIFICATION¶

DM is classified on the basis of the pathogenic process leading to hyperglycemia. There are two broad categories designated as type 1 or type 2 DM. However, there is increasing recognition of other forms where the molecular pathogenesis is better understood and may be associated with single-gene defects or combinations of genetic loci.

Table 415-1: Etiologic Classification of Diabetes Mellitus¶

Category	Description/Subtypes
I. Type 1 DM	Immune-mediated beta cell destruction, usually leading to absolute insulin deficiency
II. Type 2 DM	May range from predominantly insulin resistance with relative insulin deficiency to predominantly insulin secretory defect with insulin resistance
III.A. Genetic defects of beta cell function (MODY)	HNF-4a, Glucokinase, HNF-1a, Insulin promoter factor-1, HNF-1b, NeuroD1, KLF11, PAX4, BLK, GATA4, GATA6, SLC2A2 (GLUT2), GLIS3, Mitochondrial DNA
III.B. Neonatal diabetes	Onset <6 months; mutations in ATP-sensitive K+ channel subunits, RFX6, insulin
III.C. Transient neonatal diabetes	Temporary form of neonatal diabetes
III.D. Diseases of exocrine pancreas	Pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, carboxyl ester lipase mutations
III.E. Genetic defects in insulin action	Type A insulin resistance, leprechaunism, Rabson-Mendenhall syndrome, lipodystrophy syndromes
III.F. Endocrinopathies	Acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma
III.G. Drug/chemical-induced	Glucocorticoids, calcineurin/mTOR inhibitors, pentamidine, nicotinic acid, statins, HIV therapies, diazoxide, b-agonists, thiazides, PCSK9 inhibitors, hydantoins, asparaginase, a-interferon, antipsychotics, epinephrine, vacor
III.H. Infections	Congenital rubella, cytomegalovirus, coxsackievirus
III.I. Uncommon immune-mediated	Stiff-person syndrome, anti-insulin receptor antibodies, immune checkpoint inhibitor-related diabetes
III.J. Genetic syndromes	Wolfram, Down's, Klinefelter's, Turner's, Friedreich's ataxia, Huntington's, Laurence-Moon-Biedl, myotonic dystrophy, porphyria, Prader-Willi
IV. Gestational DM	Glucose intolerance developing during pregnancy

3.1 Type 1 DM¶

Results from autoimmunity against insulin-producing beta cells
Leads to insulin deficiency
Preceded by period of progressive worsening of glucose homeostasis
Now classified into three stages based on autoantibody development and dysglycemia

3.2 Type 2 DM¶

Heterogeneous group of disorders
Variable degrees of insulin resistance, impaired insulin secretion, and increased hepatic glucose production
Preceded by prediabetes (IFG or IGT)
Both defects in insulin action and secretion contribute to hyperglycemia phenotype

3.3 Gestational DM (GDM)¶

Glucose intolerance developing during second or third trimester of pregnancy
Related to metabolic and hormonal changes of pregnancy
IDF estimates 16% of pregnancies worldwide affected by GDM or preexisting DM (2021)
Diabetes diagnosed in first trimester should be classified as preexisting pregestational diabetes
Most women revert to normal glucose tolerance postpartum
35-60% risk of developing DM in the next 10-20 years
Children born to mothers with GDM have increased risk of metabolic syndrome and type 2 DM
ADA recommends lifelong screening every 3 years for women with history of GDM

3.4 Atypical Diabetes¶

Forms with features of both type 1 and type 2 DM, distinct from monogenic forms: - Type 2 DM phenotype before puberty - Type 2 DM phenotype in very lean individuals - Type 1 DM phenotype without autoantibodies - Ketosis-prone diabetes: presents with ketoacidosis but does not require long-term insulin (often African American or Asian heritage)

4. DIAGNOSIS¶

Glucose tolerance is classified into three broad categories: normal glucose homeostasis, impaired glucose homeostasis (prediabetes), or DM. DM is defined as the level of glycemia at which diabetes-specific complications (e.g., retinopathy) occur rather than deviation from a population-based mean. Abnormalities on screening tests should be repeated before making a definitive diagnosis unless acute metabolic derangements or markedly elevated plasma glucose are present. The diagnostic criteria also allow for withdrawal of the DM diagnosis when glucose intolerance reverts to normal.

Diagnostic Criteria for Glucose Homeostasis Categories¶

Parameter	Normal	Prediabetes	Diabetes
HbA1c	<5.6% (<41 mmol/mol)	5.7-6.4% (42-47 mmol/mol)	‡6.5% (‡48 mmol/mol)
Fasting Plasma Glucose	<5.6 mmol/L (<100 mg/dL)	5.6-6.9 mmol/L (100-125 mg/dL)	‡7.0 mmol/L (‡126 mg/dL)
2-h Plasma Glucose (OGTT)	<7.8 mmol/L (<140 mg/dL)	7.8-11.0 mmol/L (140-199 mg/dL)	‡11.1 mmol/L (‡200 mg/dL)
Random Plasma Glucose + Symptoms	—	—	‡11.1 mmol/L (‡200 mg/dL)

4.1 Diagnostic Criteria¶

The diagnosis of DM can be made using any of the following criteria: 1. HbA1c ≥ 6.5% ( ≥ 48 mmol/mol) 2. Fasting plasma glucose (FPG) ≥ 7.0 mmol/L (126 mg/dL) 3. 2-hour plasma glucose ≥ 11.1 mmol/L (200 mg/dL) after 75g OGTT 4. Random plasma glucose ≥ 11.1 mmol/L (200 mg/dL) with classic symptoms (polyuria, polydipsia, weight loss) Notes: - HbA1c should be performed in approved laboratory using NGSP-certified method - Fasting = no caloric intake for ≥ 8 hours - In absence of unequivocal hyperglycemia, criteria should be confirmed by repeat testing on different day

4.2 Prediabetes Criteria¶

Impaired glucose homeostasis (prediabetes) includes: - HbA1c: 5.7-6.4% (42-47 mmol/mol) - Impaired Fasting Glucose (IFG): FPG 5.6-6.9 mmol/L (100-125 mg/dL) - Impaired Glucose Tolerance (IGT): 2-h PG 7.8-11.0 mmol/L (140-199 mg/dL) Note: WHO defines IFG as FPG >6.1 mmol/L (110 mg/dL) Progression risk: HbA1c 6.0-6.5% associated with 25.5% 5-year risk of type 2 DM

4.3 Normal Glucose Tolerance¶

HbA1c <5.6% (<41 mmol/mol)
FPG <5.6 mmol/L (100 mg/dL)
2-h PG <7.8 mmol/L (140 mg/dL)

4.4 Special Considerations for HbA1c¶

Conditions that may influence HbA1c: - Hemoglobinopathies - Ancestry/ethnicity OGTT preferred over HbA1c for: - Cystic fibrosis-related diabetes screening (beginning age 10) - Posttransplantation diabetes screening - Gestational diabetes screening

5. SCREENING RECOMMENDATIONS¶

Widespread use of HbA1c or FPG as screening tests for type 2 DM is recommended because: 1. Large number of individuals meeting DM criteria are asymptomatic and unaware of the disorder 2. Epidemiologic studies suggest type 2 DM may be present up to a decade before diagnosis 3. Some individuals have diabetes-specific complications at time of diagnosis 4. Treatment may favorably alter natural history 5. Diagnosis of prediabetes should spur prevention efforts

Table 415-2: Criteria for Screening for Type 2 DM in Adults¶

Criterion	Details
1. Overweight/obese with risk factors	BMI ‡25 kg/m² (‡23 in Asian Americans) PLUS any: family history (parent/sibling with T2DM), high-risk ethnicity, hypertension (‡130/80 mmHg), HDL <35 mg/dL or TG >250 mg/dL, PCOS or acanthosis nigricans, history of CVD, physical inactivity, severe obesity
2. Previously identified dysglycemia	IFG, IGT, or HbA1c 5.7-6.4%: screen ANNUALLY
3. History of GDM	Screen at least every 3 years
4. All other individuals	Initiate testing at age 35 years, repeat every 3 years
5. High-risk medications	HIV medications, second-generation antipsychotics, glucocorticoids
6. History of pancreatitis	Screen within 3-6 months of pancreatitis episode
7. Cystic fibrosis	Begin at age 10; OGTT recommended
8. After organ transplantation	OGTT recommended

6. PATHOPHYSIOLOGY: TYPE 1 DM¶

Type 1 DM results from interactions of genetic, environmental, and immunologic factors that ultimately lead to immune-mediated destruction of pancreatic beta cells and insulin deficiency. Type 1 DM can develop at any age; recent data estimate ~40% of individuals develop type 1 DM after age 30. Many with adult-onset type 1 DM are initially misdiagnosed as type 2 DM.

6.1 Staging of Type 1 DM¶

Three distinct stages based on autoantibody development and dysglycemia: Stage 1: - Two or more islet cell autoantibodies (ICAs) - Normoglycemia maintained - No clinical symptoms Stage 2: - Continued autoimmunity (multiple ICAs) - Development of dysglycemia - No clinical symptoms Stage 3: - Hyperglycemia exceeding diagnostic criteria for diabetes - Clinical symptoms present

6.2 Genetic Factors¶

Concordance in identical twins: 30-70%
Major susceptibility gene: HLA region on chromosome 6 (accounts for ~50% of genetic risk) High-risk HLA haplotypes:
DRB10301-DQB10201 (DR3-DQ2)
DRB10401-DQB10302 (DR4-DQ8) Protective HLA haplotypes:
DRB1*1501
DQA10102-DQB1 Additional susceptibility loci (>60 identified):
Insulin gene promoter region
CTLA-4 gene
Interleukin 2 receptor
PTPN22 Family risk:
1-9% if parent has type 1 DM
6-7% if sibling has type 1 DM
80% have no relative with the disorder

6.3 Immunologic Mechanisms¶

Evidence of islet-directed autoimmunity: 1. Islet cell autoantibodies (ICAs) - present in >85% at diagnosis 2. Activated lymphocytes in islets and peripancreatic lymph nodes 3. T lymphocyte proliferation with islet protein stimulation 4. Cytokine release within insulitis Autoantibody targets: - Insulin - Glutamic acid decarboxylase (GAD) - Islet antigen 2 (IA-2) - Zinc transporter 8 (ZnT8) Progression risk with multiple ICAs: - ~70% risk of type 1 DM after 10 years of follow-up - >80% risk after 15 years of follow-up Mechanisms of beta cell destruction: - CD8+ T cell-mediated cytotoxicity (primary mechanism) - Toxic effects of cytokines (TNF- α , interferon γ , IL-1) - Reactive oxygen species from infiltrating immune cells

6.4 Environmental Factors¶

Putative triggers (none conclusively linked): - Viruses: coxsackie, rubella, enteroviruses - Bovine milk proteins - Nitrosourea compounds - Vitamin D deficiency - Environmental toxins - Microbiome alterations

6.5 Clinical Presentation¶

Often dramatic, acute symptoms with marked hyperglycemia
25-50% present with diabetic ketoacidosis (DKA)
"Honeymoon" phase may occur with reduced insulin requirements
Other islet cell types (alpha, delta, PP cells) are spared from autoimmune destruction
Alpha cell dysfunction: fasting/postprandial hyperglucagonemia but impaired glucagon response to hypoglycemia

Rare form (<1% of treated individuals)
Rapid onset, often with DKA
Occurs after anti-PD-1, anti-PD-L1, ± anti-CTLA-4 therapy
Variable time after treatment initiation
Insulin therapy required

7. PATHOPHYSIOLOGY: TYPE 2 DM¶

Type 2 DM likely encompasses a range of disorders with the common phenotype of hyperglycemia. It is characterized by: - Impaired insulin secretion - Insulin resistance - Excessive hepatic glucose production - Abnormal fat metabolism - Systemic low-grade inflammation Obesity, particularly visceral or central, is present in ≥ 80% of patients.

7.1 Genetic Factors¶

Concordance in identical twins: 70-90%
~70% risk if both parents have type 2 DM
Polygenic and multifactorial
600 genetic loci identified (relative risk 1.06-1.5)
Most prominent: variant of transcription factor 7-like 2 gene
<10% of genetic risk currently explained by identified loci
In utero environment contributes (both increased and reduced birth weight increase risk)

7.2 Insulin Resistance¶

Insulin resistance = decreased ability of insulin to act on target tissues (muscle, liver, fat) - Results from genetic susceptibility, obesity, and metabolic inflammation - Relative, not absolute (supranormal insulin can normalize glucose) - Glucose utilization 30-60% lower than nondiabetic individuals Mechanisms: - Postreceptor defects in insulin-regulated phosphorylation/dephosphorylation - Accumulation of lipid intermediates in skeletal myocytes - Impaired mitochondrial oxidative phosphorylation - Reduced insulin-stimulated mitochondrial ATP production - Impaired fatty acid oxidation - Reactive oxygen species generation - Metabolic inflammation

7.3 Impaired Insulin Secretion¶

Initially increases to compensate for insulin resistance
First-phase secretion greatly reduced
Response to nonglucose secretagogues (arginine) initially preserved
Beta cell function reduced ~50% at onset of type 2 DM
Increased proinsulin secretion reflects processing abnormalities
Progressive decline over time Factors contributing to beta cell dysfunction:
Genetic defects (second hit theory)
Islet amyloid (IAPP) deposition
Glucose toxicity
Lipotoxicity
Proinflammatory cytokines from islet macrophages

7.4 Hepatic Glucose and Lipid Production¶

Failure of hyperinsulinemia to suppress gluconeogenesis
Results in fasting hyperglycemia
Decreased postprandial glycogen storage
Increased lipolysis and free fatty acid flux
Increased VLDL-triglyceride synthesis
May lead to metabolic dysfunction-associated steatotic liver disease (MASLD)

7.5 Role of Adipose Tissue¶

Adipokines secreted by adipocytes: - Free fatty acids (elevated) - Retinol-binding protein 4 - Leptin - TNF- α - Resistin - IL-6 - Adiponectin (reduced in obesity - insulin-sensitizing) Additional factors: - Adipose-resident macrophages contribute to metabolic inflammation - Visceral fat drainage via portal circulation affects liver directly

7.6 Ethnic Variations¶

Latinos: greater insulin resistance
East Asians and South Asians: more beta cell dysfunction
East/South Asians: develop T2DM at younger age, lower BMI, greater visceral adiposity
African Americans: more prone to nonketotic hyperosmolar presentation

8. REGULATION OF GLUCOSE HOMEOSTASIS¶

Glucose homeostasis reflects a balance between energy intake from ingested food, hepatic glucose production (gluconeogenesis), and peripheral tissue glucose uptake/utilization. Insulin is the most important regulator, but neural input, metabolic signals, and other hormones (glucagon) provide integrated control.

8.1 Fasting State¶

Low insulin levels + modest glucagon increases
Increased hepatic gluconeogenesis and glycogenolysis
Reduced glucose uptake in insulin-sensitive tissues (muscle, fat)
Increased mobilization of gluconeogenic precursors (amino acids, free fatty acids)

8.2 Fed State¶

Postprandial glucose load elicits insulin rise and glucagon fall
Suppression of hepatic glucose production
Increased hepatic glucose uptake
Major portion of postprandial glucose utilized by skeletal muscle (insulin-stimulated)
Brain utilizes glucose in insulin-independent manner

8.3 Insulin Biosynthesis¶

Produced by pancreatic beta cells
Initially synthesized as 86-amino-acid preproinsulin
Proteolytic processing removes signal peptide → proinsulin
Cleavage of 31-residue C-peptide generates A chain (21 aa) and B chain (30 aa)
Mature insulin and C-peptide co-secreted from granules
C-peptide cleared more slowly than insulin → useful marker Islet Amyloid Polypeptide (IAPP/Amylin):
37-amino-acid peptide co-secreted with insulin
Major component of islet amyloid in type 2 DM

8.4 Insulin Secretion Mechanism¶

Glucose-stimulated insulin secretion pathway: 1. Glucose enters beta cell via GLUT transporters 2. Glucokinase phosphorylates glucose (rate-limiting step) 3. Metabolism generates ATP 4. ATP inhibits ATP-sensitive K+ channel 5. Membrane depolarization 6. Opening of voltage-dependent calcium channels 7. Calcium influx stimulates insulin secretion Two phases of secretion: - First phase: rapid response - Second phase: more prolonged - Impaired first-phase response is earliest detectable abnormality in both type 1 and type 2 DM Amplification of secretion: - GLP-1 and GIP (incretins): bind beta cell receptors, stimulate secretion via cAMP - Only effective when blood glucose above fasting level - Also suppress glucagon production

8.5 Insulin Action¶

Secreted into portal venous system
~50% cleared by liver in first pass (portal:peripheral ratio ~2:1)
Binds receptors on peripheral target tissues (muscle, adipose)
Stimulates receptor tyrosine kinase activity → autophosphorylation
Activates insulin receptor substrates (IRS)
PI3-kinase pathway → GLUT4 translocation → glucose uptake
Other pathways → glycogen synthesis, protein synthesis, lipogenesis, gene regulation

9. OTHER SPECIFIC FORMS OF DIABETES¶

Other etiologies include specific genetic defects in insulin secretion or action, metabolic abnormalities impairing insulin secretion, mitochondrial abnormalities, and various conditions impairing glucose tolerance.

9.1 Monogenic Diabetes (MODY)¶

Characteristics: - Autosomal dominant inheritance - Early onset of hyperglycemia (usually <25 years; sometimes neonatal) - Impaired insulin secretion Common mutations and features: HNF-4 α (MODY 1): - Progressive decline in glycemic control Glucokinase (MODY 2): - Mild-to-moderate stable hyperglycemia - Does not respond to oral agents - Usually does not require treatment (except possibly in pregnancy) - Alters glucose set point for insulin secretion HNF-1 α (MODY 3): - Progressive decline in glycemic control - May respond to sulfonylureas - Some initially diagnosed as type 1 DM HNF-1 β : - Progressive insulin secretion impairment + hepatic insulin resistance - Requires insulin (minimal response to sulfonylureas) - Associated abnormalities: renal cysts, mild pancreatic exocrine insufficiency, abnormal LFTs

9.2 Neonatal Diabetes¶

Onset <6 months of age
Heterogeneous group affecting beta cell function/pancreatic development Causes:
Activating mutations in ATP-sensitive K+ channel subunits (Kir6.2, ABCC8) - may respond to sulfonylureas
GATA6 mutations - most common cause of pancreatic agenesis
Glucokinase homozygous mutations - severe neonatal form
Mitochondrial DNA mutations - associated with deafness
Insulin gene mutations (MIDY - Mutant Ins-gene-induced diabetes of youth) Screening: Any individual with diabetes onset <6 months should have genetic screening

9.3 Pancreatic Disease and Diabetes¶

Types 3c/Pancreatic/Pancreatogenic DM: - Pancreatitis, pancreatectomy, pancreatic neoplasia - Cystic fibrosis (prevalence ~50% with improved survival) - Hemochromatosis, fibrocalculous pancreatopathy Pathogenesis: - Islet damage/destruction - Insulin and glucagon deficiency - Pancreatic exocrine-endocrine interaction Management: - Insulin is preferred therapy in most forms - Pancreatitis episode should prompt diabetes screening

9.4 Insulin Resistance Syndromes¶

Metabolic Syndrome/Insulin Resistance Syndrome: - Hypertension - Dyslipidemia (decreased HDL, elevated triglycerides) - Central/visceral obesity - Type 2 DM or IGT/IFG - Accelerated cardiovascular disease Type A Insulin Resistance: - Affects young women more severely - Severe hyperinsulinemia, obesity, hyperandrogenism features - Undefined defect in insulin signaling pathway Type B Insulin Resistance: - Middle-aged women - Severe hyperinsulinemia, hyperandrogenism features, autoimmune disorders - Autoantibodies against insulin receptor - May cause intermittent hypoglycemia Polycystic Ovary Syndrome (PCOS): - Chronic anovulation, hyperandrogenism - Insulin resistance in significant subset - Increased risk of type 2 DM independent of obesity Lipodystrophies: - Selective loss of adipose tissue - Severe insulin resistance and hypertriglyceridemia - Can be inherited or acquired

9.5 COVID-19 and DM¶

Hyperglycemia more common in SARS-CoV-2 infection
Presence of DM worsens COVID-19 outcomes
SARS-CoV-2 most likely does not directly cause beta cell destruction
Increases DM ascertainment and creates conditions worsening hyperglycemia

10. PREVENTION OF TYPE 2 DM¶

Type 2 DM is preceded by a period of prediabetes (IGT or IFG), and multiple interventions can prevent or delay onset. Individuals with prediabetes should be referred to structured programs for weight reduction and increased physical activity, and considered for weight-lowering medications.

10.1 Lifestyle Intervention¶

Diabetes Prevention Program (DPP) Results: - Intensive lifestyle changes: 58% reduction in T2DM development vs placebo - Diet + exercise (30 min/day, 5 times/week) - 5-7% body weight loss during 3-year study - Effects persisted for at least 15 years - Effective regardless of age, sex, or ethnic group Similar efficacy demonstrated in Finnish and Chinese populations

10.2 Pharmacologic Prevention¶

Agents that prevent or delay type 2 DM: - Metformin: 31% reduction vs placebo (DPP) - α -glucosidase inhibitors - Thiazolidinediones - GLP-1 receptor pathway modifiers - SGLT-2 inhibitors - Orlistat Emerging approaches: - GLP-1 receptor agonists (greater weight loss) - Combined GLP-1/GIP receptor agonist (tirzepatide) - Intensive very-low-calorie diet interventions

11. DISEASE-MODIFYING THERAPY FOR TYPE 1 DM¶

There is increased emphasis on identifying high-risk individuals with multiple ICAs to allow earlier intervention.

11.1 Teplizumab¶

Fc receptor-nonbinding anti-CD3 monoclonal antibody
FDA-approved for stage 2 type 1 DM
Single 14-day course
Delayed onset of stage 3 type 1 DM by median of 32.5 months
For high-risk individuals with multiple autoantibodies and dysglycemia
Being used by selected centers

11.2 Screening Approach¶

ICA screening rapidly evolving and becoming more widely available
Target: first-degree relatives of individuals with type 1 DM; general population screening emerging
If ICAs detected: refer to specialized center for dysglycemia testing and possible treatment

12. CLINICAL APPROACH TO THE PATIENT¶

Once DM diagnosis is made, attention should be directed to symptoms (acute and chronic) and classifying the type of diabetes. Symptoms secondary to acute hyperglycemia may occur at any stage; those related to chronic hyperglycemia typically begin appearing during the second decade of hyperglycemia.

Features Distinguishing Type 1 vs Type 2 DM¶

Feature	Type 1 DM	Type 2 DM
Age at onset	Often <35 years (can be any age)	Often >35 years (decreasing)

Feature	Type 1 DM	Type 2 DM
Body habitus	Often lean (increasingly overweight)	Often obese (80%)
Presentation	Acute, often DKA (25-50%)	Insidious; may have complications at diagnosis
Ketosis tendency	Yes	Uncommon (except ketosis-prone type 2)
Autoantibodies	Present in >85%	Usually absent (5-10% have markers)
C-peptide	Low/undetectable	Normal to elevated initially
Insulin requirement	Absolute, for survival	Not initially required
Associated conditions	Other autoimmune disorders	Insulin resistance, HTN, CVD, dyslipidemia, PCOS
Family history	Often negative (>80%)	Often positive

12.1 History¶

Complete medical history with DM-relevant emphasis: - Current weight and recent changes - Family history of DM and complications - Sleep history - Cardiovascular disease risk factors - Exercise habits - Smoking status - History of pancreatic disease - Ethanol use Symptoms of hyperglycemia: - Polyuria, polydipsia - Weight loss - Fatigue, weakness - Blurry vision - Frequent superficial infections (vaginitis, fungal skin infections) - Slow healing of skin lesions For established DM: - Symptoms at initial diagnosis (helps confirm correct type classification) - Prior therapies and intolerance - Prior HbA1c levels - Self-monitoring glucose results - Frequency of hypoglycemia (<3.0 mmol/L, <54 mg/dL) - Presence of DM-specific complications - Patient's knowledge about diabetes, exercise, nutrition, sleep Women of childbearing age: - Ascertain pregnancy plans - Counsel on importance of tight glycemic control (HbA1c <6.5%) prior to conception

12.2 Physical Examination¶

DM-relevant components: - Weight and BMI - Retinal examination - Orthostatic blood pressure - Foot examination - Peripheral pulses - Insulin injection sites - Teeth and gums (periodontal disease more frequent in DM) Annual Foot Examination: 1. Assess blood flow: pedal pulses 2. Assess sensation: vibratory (128-Hz tuning fork at base of great toe), monofilament (5.07, 10-g), pinprick, ankle reflexes, nail care 3. Look for deformities: hammer/claw toes, Charcot foot 4. Identify potential ulceration sites Neuropathy Screening: - Distal symmetric polyneuropathy: screen from initial diagnosis - Autonomic neuropathy: screen 5 years after type 1 DM diagnosis; at diagnosis for type 2 DM - Goal: detect loss of protective sensation (LOPS)

12.3 Classification in Individual Patients¶

Features suggesting Type 1 DM: - Younger age at diagnosis (<35 years) - Nonobese BMI - Ketoacidosis - Markedly elevated plasma glucose at diagnosis - Family or personal history of autoimmune disorders (thyroid disease, adrenal insufficiency, pernicious anemia, celiac disease, vitiligo) Features suggesting Type 2 DM: - Obesity (80% are obese; elderly and Asian patients may be lean) - May not require insulin initially - Associated conditions: insulin resistance, hypertension, CVD, dyslipidemia, PCOS - Abdominal obesity, hypertriglyceridemia Consider Monogenic Diabetes if: - Diabetes onset in childhood or early adulthood - Diagnosed within first 6 months of life - Autosomal pattern of diabetes inheritance - Diabetes without typical type 1 or type 2 features - Stable mild fasting hyperglycemia Important considerations: - Many individuals with type 1 DM are now overweight/obese - 5-10% with type 2 phenotype have autoimmune markers (autoimmune diabetes of adults) - Some with type 2 phenotype present with DKA (ketosis-prone type 2 DM)

12.4 Laboratory Assessment¶

Initial assessment: 1. Confirm diagnosis meets DM criteria 2. Assess degree of glycemic control (HbA1c) 3. Standard laboratory evaluation 4. Screen for DM-associated conditions: - Albuminuria - Dyslipidemia - Thyroid dysfunction Tests to aid classification: - C-peptide: low level with elevated glucose suggests insulin requirement; cannot completely distinguish type 1 from type 2 - Islet cell antibodies: useful at diabetes onset if type unclear

13. KEY POINTS & CLINICAL PEARLS¶

Clinical Pearls for Diabetes Mellitus¶

Topic	Key Point
Diagnosis	Abnormalities on screening tests should be repeated before definitive diagnosis unless acute metabolic derangements present
Type 1 staging	Stage 1 = 2+ autoantibodies with normoglycemia; Stage 2 = autoantibodies + dysglycemia; Stage 3 = clinical diabetes
Adult-onset type 1	~40% of type 1 DM develops after age 30; many initially misdiagnosed as type 2
Prediabetes progression	HbA1c 6.0-6.5% carries 25.5% 5-year risk of progressing to T2DM
Prevention	Lifestyle modification (diet + 30 min exercise 5x/week) prevents 58% of T2DM; effects last >15 years
Beta cell function	First-phase insulin response impairment is earliest detectable abnormality in both type 1 and type 2 DM
Hepatic glucose	Increased hepatic glucose production accounts for elevated FPG; decreased peripheral utilization causes postprandial hyperglycemia
Monogenic diabetes	Consider genetic screening for diabetes onset <6 months; atypical features; autosomal inheritance pattern; stable mild hyperglycemia
Sulfonylurea response	Some patients with MODY 3 (HNF-1a) or neonatal diabetes (K+ channel mutations) respond to sulfonylureas and may discontinue insulin
HbA1c limitations	May be affected by hemoglobinopathies and ancestry; use OGTT for cystic fibrosis, posttransplantation, and GDM screening
Teplizumab	FDA-approved for stage 2 type 1 DM; delays stage 3 onset by median 32.5 months
Foot exam	Annual screening for LOPS; test vibratory sensation with 128-Hz tuning fork at base of great toe + 10-g monofilament
Pregnancy	Counsel women on importance of HbA1c <6.5% prior to conception; screen women with GDM history every 3 years for life