Diabetes Mellitus

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of 𝛽 cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance, as well as relative insulin deficiency. Genetically determined causes of diabetes (e.g., maturity-onset diabetes of the young and late autoimmune diabetes in adults) are being increasingly recognized, but they make up a small portion of cases. There is no definitive cure for DM. The objective of management is the prevention of complications, which may include coronary artery disease, CKD, retinopathy, and neuropathy. Long-term monitoring and maintenance of optimal blood glucose levels are key to preventing complications. Treatment is specific to the type of diabetes, with glycemic control as the goal in all types; insulin replacement is essential in type 1, and a healthy diet, lifestyle changes, and medications are important in type 2.

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Definition

Diabetes mellitus (DM) is a disorder of carbohydrate metabolism. Diabetes mellitus usually occurs in genetically predisposed individuals and is characterized by inadequate production of insulin or resistance to insulin’s action on the pancreas. These features result in hyperglycemia and the long-term pathologic sequelae of DM.

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Epidemiology

Type 1

  • Nearly 1.6 million people in the United States affected in 2018
  • Typically presents in children or adults < 25 years of age
  • 5%–10% of all diabetics
  • Has a strong age, race, and geographic bias:
    • Most commonly diagnosed at ages 4–6 years, with 2nd peak in early teenage years
    • Highest geographic density in Finland and Sardinia
    • In the United States, predominantly seen in non-Hispanic White children and adolescents
  • Genetic predisposition

Type 2

  • In 2017, estimated worldwide prevalence was 425 million people
  • Usually presents at ages > 40 years but can be earlier
  • 90%–95% of diabetics
  • Estimated prevalence 10.5% in the United States (and 27% in Americans > 65 years)
  • Incidence much higher in Native Americans, Blacks, Hispanics, Asian Americans, and Pacific Islanders

Gestational diabetes

  • Occurs in 5%–7% of pregnancies in the United States
  • Ethnic and geographic prevalences mirror those of type 2 DM
  • In the United States, elevated prevalence in African American, Hispanic American, Native American, Pacific Islander, and South or East Asian women
  • Increased incidence of nongestational diabetes later in life

Risk factors:

  • Hemoglobin A1c ≥ 5.7% or elevated fasting glucose level prior to pregnancy
  • Gestational diabetes in previous pregnancy
  • ≥ 110% of ideal body weight or BMI (weight in kilograms divided by square of the height in meters) > 30 during gestation
  • Gaining excessive weight during 1st half of gestation
  • Family history of DM
  • Glucose in urine at 1st prenatal visit
  • Previous children ≥ 4 kg at birth 
  • Abnormal lipid studies
  • Polycystic ovary syndrome (PCOS)
  • Use of glucocorticoids
  • Multiple (twin, triplet, etc.) gestation

Late Autoimmune Diabetes in Adults (LADA)

  • Presents in adulthood: > age 25
  • 2%–12% of type 2 DM in the adult population

Maturity Onset Diabetes of the Young (MODY)

  • Affects 1%–5% of all patients with diabetes mellitus
  • No reported ethnic predilection

Etiology

Type 1

  • Autoimmune destruction of pancreatic 𝛽 cells by glutamic acid decarboxylase (GAD) antibodies leading to insulin deficiency
  • HLA-linked (HLA-DQ, HLA-DR3, and HLA-DR4) 
  • Associated with other autoimmune conditions

Type 2

  • Caused by insulin resistance 
  • Relative insulin deficiency
  • Strong family history/genetic component

Gestational diabetes

  • Unclear etiology, but not autoimmune
  • Increased insulin secretion but not sufficient to maintain normal glucose levels
  • Decreased insulin sensitivity

Late autoimmune diabetes in adults

  • Similar to type 1 diabetes, LADA is closely linked to genes in the HLA complex
  • Obesity and other factors that cause insulin resistance

Maturity onset diabetes of the young

  • Autosomal dominant inheritance
  • 14 distinct subtypes 
  • Mechanisms involved:
    • Defective transcriptional regulation
    • Abnormal metabolic enzymes
    • Protein misfolding
    • Dysfunctional ion channels
    • Impaired signal transduction

Pathophysiology

Type 1

  • T-cell immune-mediated destruction of insulin-producing pancreatic islet cells
  • Autoantibodies (not always detectable):
    • GAD autoantibodies:
      • Target insulin-producing pancreatic 𝛽 cells 
      • Autoimmune destruction of 80%–90% of cells
      • Leads to insulin deficiency and hyperglycemia.
    • Islet cell cytoplasmic autoantibodies (ICA)
    • Insulinoma-associated-2 (IA-2) autoantibodies 
    • Insulin autoantibodies (IAAs)
    • Zinc transporter-8 autoantibodies (ZnT8A)
  • Patients have minimal to no autonomous insulin production:
    • Require insulin replacement at all times to treat hyperglycemia 
    • Failure to supplement insulin leads to:
      • Diabetic ketoacidosis (DKA) (can be life-threatening)
      • Chronic complications of diabetes

Type 2

Type 2 DM is a combination of defective insulin secretion and decreased insulin sensitivity.

  • Defective insulin secretion:
    • Insulin secretion by 𝛽 cells requires glucose transport into the cell
    • Mediated by glucose transporter 2 (GLUT-2)
    • Obesity and high-fat diet may affect this transport, causing decreased insulin secretion
  • Peripheral insulin resistance:
    • With constant high intake of glucose, there is a constant high demand for insulin. 
    • Hyperinsulinemia leads to decrease in sensitivity of the insulin receptors in liver, muscle, and adipose cells.
    • Down-regulation of receptors leads to vicious cycle of high insulin levels.
  • Additional mechanisms:
    • Impaired hepatic sensitivity to insulin leads to lack of inhibition of glycogenolysis and gluconeogenesis
    • Hyperglycemia can impair pancreatic 𝛽-cell function and exacerbate insulin resistance.
    • High demand for insulin and excessive production of pancreatic enzymes causes pro-amylin accumulation and pancreatic apoptosis.
    • Progressive pancreatic 𝛽-cell failure

There are several effects of chronic hyperglycemia:

  • High serum glucose level (> 180 mg/dL) exceeds renal threshold causing:
    • Glucosuria
    • Increase in osmotic pressure of the urine leading to polyuria
    • Dehydration leading to polydipsia
  • Intracellular glucose deficiency, causing polyphagia
  • Chronic complications of diabetes

Gestational diabetes

  • 𝛽-cell dysfunction in setting of insulin resistance (similar to type 2)
  • Defect is thought to exist prior to conception; stress from pregnancy unmasks and worsens it.
  • Effects of maternal hyperglycemia on pregnancy:
    • Increased risk for preeclampsia
    • Increased risk for birth complicated by shoulder dystocia 
  • Effects of maternal hyperglycemia on developing fetus: 
    • Increased risk for postnatal hypoglycemia 
    • Increased risk for large-for-gestational-age fetus

Late autoimmune diabetes in adults

  • Autoimmune process (similar to type 1)
  • Autoantibody-mediated destruction of 𝛽 cells (particularly GAD)
  • Slow, progressive process 
    • Patients often not insulin-dependent at presentation
    • Oral medication rapidly loses effect
    • Eventually leads to insulin requirement 

Maturity onset diabetes of the young

  • Genetic defects leading to impaired glucose sensing and insulin secretion
  • Mutations in hepatocyte nuclear factor-4-alpha (HNF4A) cause 10% of cases of MODY.
Pancreas

Pancreas:
Pancreatic exocrine function involves the acinar cells secreting digestive enzymes that are transported into the small intestine by the pancreatic duct. The endocrine function of the pancreas involves the secretion of insulin (produced by beta cells) and glucagon (produced by alpha cells) within the pancreatic islets. These 2 hormones regulate the rate of glucose metabolism in the body. The photomicrograph shows pancreatic islets.

Image: “Pancreas” by Regents of University of Michigan Medical School. License: CC By 4.0

Clinical Presentation

Type 1

DKA:

Type 1 DM often presents urgently with DKA:

  • Usually precipitated by a “tipping” event (e.g., viral illness, trauma, emotional stress)
  • Depressed mental status
  • Abdominal pain
  • Vomiting
  • Fruity “acetone” breath

Hyperglycemia:

Type 1 DM can also present with classic symptoms of hyperglycemia:

  • Polydipsia
  • Polyphagia
  • Polyuria (can present as enuresis and nocturia in children)
  • Weight loss
  • Blurred vision 

Type 2

Type 2 DM has a gradual onset, initially remaining asymptomatic for several years:

  • High glucose levels often detected on screening tests before symptoms appear
  • Can present with classic symptoms of hyperglycemia, as in type 1 DM
  • Sometimes diagnosed with hyperosmolar hyperglycemic state or signs of long-term complications before the diagnosis is known
  • Rarely, DKA present
  • Nonspecific symptoms due to hyperglycemia: 
    • Fatigue
    • Malaise
    • Anorexia
    • Amenorrhea
    • Erectile dysfunction
    • Headache
    • Blurred vision 
    • Muscle cramps
    • Dehydration
  • Skin manifestations: 
    • Recurrent cellulitis or fungal infections
    • Poor or delayed wound healing
    • Generalized pruritus
    • Acanthosis nigricans: hyperpigmented velvet-like plaques on the skin of the axilla or neck or between the digits

Gestational diabetes

  • Because of universal screening in the United States, most cases are diagnosed before symptoms arise.
  • Usually in the 2nd or 3rd trimester
  • Untreated symptoms similar to those of type 2 DM

Late autoimmune diabetes in adults

  • Nonspecific symptoms similar to those of type 2 DM:
    • Fatigue
    • Malaise
    • Anorexia

Maturity onset diabetes of the young

  • Patients present at young age, not usually obese: often misdiagnosed as type 1
  • Not insulin-resistant:
    • Distinguishing from type 2 can be challenging
    • Characteristic symptoms of insulin resistance (e.g., acanthosis nigricans) often absent

Diagnosis

Diagnosis of diabetes is based on the presence of inappropriate hyperglycemia in the context of suspicious clinical symptoms.

Table: Diagnostic criteria for diabetes mellitus
TestNormal rangeIncreasd risk for diabetes (prediabetes)Diabetes
Random plasma glucose Classic hyperglycemic symptoms plus a random plasma glucose > 200 mg/dL
Fasting plasma glucose
(fasting 8 hours)
< 100 mg/dL 100–125 mg/dL > 126 mg/dL
Plasma glucose after a 2-hour,
75-g OGTT
< 140 mg/dL 140–199 mg/dL ≥ 200 mg/dL

Hemoglobin A1c < 5.7% 5.7%–6.4% ≥ 6.5%
OGTT: oral glucose-tolerance test

Type 1

  • Urinalysis may show microalbuminuria, glucosuria, or ketone bodies 
  • DM-related autoantibodies (anti-GAD65, ICA, anti-IA-2)
  • C-peptide
    • Low levels indicate insulin deficiency (type 1 DM)
    • High levels indicate insulin resistance (type 2 DM)

Type 2

  • Screening recommended for:
    • Patients > 45 years 
    • Younger if risk factors present
  • Diagnostic criteria: (any 1 of the following)
    • Fasting (> 8 hours) plasma glucose ≥ 126 mg/dL (prediabetes, 100–125)
    • Plasma glucose ≥ 200 mg/dL 2 hours after ingestion of 75 g of glucose (oral glucose-tolerance test (OGTT)) (prediabetes, 140–199)
    • Hemoglobin A1c (HbA1c) ≥ 6.5% (prediabetes, 5.7–6.4)
    • Random plasma glucose ≥ 200 mg/dL in a patient with classic symptoms 

Gestational diabetes

Oral glucose-tolerance test is recommended during the 24th–28th week of pregnancy. Abnormal results are:

  • Fasting glucose: ≥ 92 mg/dL
  • 1-hour glucose: ≥ 180 mg/dL 
  • 2-hour glucose: ≥ 153 mg/dL

Late autoimmune diabetes in adults

  • Same diagnostic criteria as for type 2 DM
  • GAD65 antibodies positive: helps to identify patients thought to have type 2 DM, but who will likely require insulin for glucose control

Maturity onset diabetes of the young

  • To differentiate from type 1: lack serum autoantibodies
  • To differentiate from type 2:
    • Currently no good biochemical markers
    • Family history of DM not suggestive
    • Diabetes mellitus in the absence of obesity or secondary markers of insulin sensitivity can be suggestive.
    • Genetic testing

Monitoring

Self-monitoring

  • Glucose monitoring:
    • Fasting 
    • Near meals (before and/or after, depending on patient)
    • With symptoms of hypoglycemia or hyperglycemia
    • Before important activities (e.g., flying a plane/driving a school bus)
    • New continuous glucose-monitoring systems often used in type 1 DM
  • Regular foot hygiene and self-monitoring for skin ulceration 

Clinician monitoring

  • Regular weight and BP checks
  • Lab testing of HbA1c levels yearly to evaluate glucose control and efficacy of therapy:
    • HbA1c provides an estimate of patient’s blood glucose over previous 3 months.
    • Target goal: < 7%
    • Less strict in elderly patients/children
  • Annual microalbumin : creatinine ratio urine test
  • Lipid testing annually:
    • Total cholesterol
    • HDL
    • LDL with goal < 100 mg/dL
    • Triglycerides
  • Annual retinal eye exam 
  • Prophylactic vaccines (influenza, pneumococcal)
  • Regular dental exams

Management

No definitive cure exists for diabetes. Management centers around correcting high blood glucose with insulin (type 1) or oral medication (type 2), avoiding low blood glucose, and treating the clinical effects of chronic hyperglycemia.

Multidisciplinary approach

Initial management is with patient education and support.

  • Lifestyle modifications: 
    • Balanced diet 
    • Regular exercise
    • Weight loss with reduced caloric intake if overweight or obese
  • Smoking cessation to decrease the risk of comorbid complications
  • Stress management
  • Pharmacologic therapies to meet individualized glycemic goals:
    • Choice of medication depends on the level of HbA1c at the time of diagnosis
    • Need to be adjusted with CKD or intolerance

Oral medications

 Classes of oral medications used to treat insulin-resistant diabetes (usually type 2):

  • Biguanide (metformin): 1st-line drug of choice
  • Sodium–glucose cotransporter-2 (SGLT-2) inhibitors: demonstrated benefit for cardiorenal outcomes, especially for heart failure hospitalization, risk of kidney disease progression, and mortality
  • Dipeptidyl peptidase-4 (DPP-4) inhibitors
  • Sulfonylureas
  • Thiazolidinediones

Insulin therapy

Insulin therapy is used to treat type 1 DM and sometimes type 2 DM when oral medications alone are no longer sufficient.

  • Rapid-acting insulins: start working in 10–15 minutes
    • Glulisine (brand name Apidra)
    • Lispro (brand name Humalog)
    • Aspart (brand name NovoLog)
  • Short-acting insulin: 
    • Starts working in 30 minutes, peaks at 2–3 hours
    • Rapid-acting and short-acting insulins are used in combination with longer-acting insulins or in insulin pumps for type 1 diabetes
  • Long-acting insulin: last 12–24 hours
    • NPH (generic, stands for neutral protamine Hagedorn)
    • Glargine (brand name Lantus or Basaglar)
    • Detemir (brand name Levemir)

Noninsulin injectable therapies

  • Glucagon-like peptide-1 (GLP-1) receptor agonists: preferred in patients who already have cardiac or renal comorbidities:
    • Exenatide (brand name Byetta)
    • Dulaglutide (brand name Trulicity)
    • Liraglutide (brand name Victoza)
    • Semaglutide (Ozempic) — also available in tablet form (Rybelsus)
  • Amylin mimetic pramlintide (brand name Symlin) (not often used):
    • Suppresses plasma glucagon secretion
    • Slows gastric emptying
    • Promotes satiety

Special considerations with insulin use

The dawn phenomenon:

  • Early in the morning, the effect of exogenous insulin injected the day before disappears.
  • Insulin-antagonistic hormones increase physiologically in the morning.
  • May cause morning hyperglycemia

The Somogyi effect:

  • Rebound morning hyperglycemia
  • Response to hypoglycemia during the night after excessive amounts of exogenous insulin the evening before

Complications

Potential complications

Type 1:

  • DKA:
    • Severe hyperglycemia
    • Presents with vomiting, shallow respirations, and confusion
    • Elevation of serum beta-hydroxybutyrate and urine ketones is diagnostic.
    • Can lead to coma and death if untreated
    • Requires hospitalization
  • Severe insulin-induced hypoglycemia:
    • Confusion
    • Irritability
    • Anxiety
    • Slurred speech
    • Diplopia
    • Can lead to loss of consciousness, seizures, or death if untreated
    • Treat with glucagon injection or nasal administration.

Type 2:

  • Hyperosmolar hyperglycemic state (HHS): 
    • Severe hyperglycemia results in high osmolarity without significant ketoacidosis. 
    • Symptoms include signs of dehydration, weakness, leg cramps, vision problems, and altered level of consciousness.
    • Requires hospitalization
  • Insulin-associated weight gain and potential causes:
    • Continued dietary indiscretion
    • Reduction in glycosuria with now improved glycemic control
    • Snacking to support an insulin dose that is too high (overtreatment of hypoglycemia)
    • Weight gain worsens insulin resistance and may prompt insulin dose escalation, leading to a vicious cycle.

Gestational diabetes:

The risk of complications is proportional to the level of hyperglycemia:

  • Miscarriage
  • Fetal deformities
  • Large-for-gestational-age fetus, often requiring cesarean delivery
  • Macrosomia
  • Preeclampsia
  • Hypoglycemia in the infant

Chronic complications

Both type 1 and type 2 DM can cause diabetic complications.

  • Macrovascular disease: 
    • Coronary heart disease/acute MI
    • Cerebrovascular disease/stroke
    • Peripheral artery disease/claudication
  • Microvascular disease: 
    • CKD
    • Diabetic retinopathy
    • Neuropathy/foot ulcers
  • Fatty liver disease

Differential Diagnosis

Type 1

  • Maturity onset diabetes of the young (MODY): clinically heterogeneous disorder characterized by non-insulin-dependent diabetes diagnosed at a young age (< 25 years) with autosomal dominant transmission and lack of autoantibodies.
  • Psychogenic polydipsia: excessive volitional water intake. Psychogenic polydipsia is often seen in patients with severe mental illness and/or developmental disability. There may be no physical effects, but hyponatremia can occur.
  • Nephrogenic diabetes insipidus: form of diabetes insipidus primarily due to kidney pathology. Nephrogenic diabetes insipidus differs from central/neurogenic diabetes insipidus, which is caused by insufficient levels of antidiuretic hormone (ADH).
  • High-output renal failure: associated with polyuria from other causes, including stress, trauma, burns, or surgery.

Type 2

  • Metabolic syndrome: group of conditions including central obesity, high BP, high blood sugar, high serum triglycerides, and low serum HDL.
  • Latent autoimmune diabetes of adulthood (LADA): form of type 1 DM. When the diagnosis is not clear, antibody testing in patients with newly manifested diabetes is helpful to establish this diagnosis.
  • Steroid-induced hyperglycemia: Prednisone and similar medications may cause significant hyperglycemia. Steroid-induced hyperglycemia may be transient and resolve with completion of the course of steroids, or it may persist and reveal underlying type 2 DM.
  • Secondary diabetes: due to Cushing’s disease, acromegaly, or glucagon hypersecretion caused by islet alpha cell tumor, Down syndrome (trisomy 21), or hemochromatosis, chronic pancreatitis, or pancreatic malignancy.

References

  1. Levitsky, L.L. (2020). Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents. UpToDate. Retrieved April 15, 2021, from https://www.uptodate.com/contents/epidemiology-presentation-and-diagnosis-of-type-1-diabetes-mellitus-in-children-and-adolescents
  2. Inzucchi, S. (2021). Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults.UpToDate. Retrieved April 15, 2021, from https://www.uptodate.com/contents/clinical-presentation-diagnosis-and-initial-evaluation-of-diabetes-mellitus-in-adults
  3. ADA. (2020). Statistics About Diabetes. Retrieved April 16, 2021, from https://www.diabetes.org/resources/statistics/statistics-about-diabetes#:~:text=Overall%20Numbers%2C%20Diabetes%20and%20Prediabetes.%20Undiagnosed%3A%20Of%20the,million%20Americans%20are%20diagnosed%20with%20diabetes%20every%20year
  4. Kühl, C. (1998). Etiology and pathogenesis of gestational diabetes. Diabetes care, 21 Suppl 2, B19-26. https://pubmed.ncbi.nlm.nih.gov/9704223/
  5. Wexler, DJ. (2020). Initial management of hyperglycemia in adults with type 2 diabetes mellitus. UpToDate. Retrieved April 16. 2021, from https://www.uptodate.com/contents/initial-management-of-hyperglycemia-in-adults-with-type-2-diabetes-mellitus
  6. Carlsson, S. (2019). Etiology and pathogenesis of latent autoimmune diabetes in adults (LADA) compared to type 2 diabetes. Frontiers in Physiology 10:320. Retrieved April 16, 2021, from https://pubmed.ncbi.nlm.nih.gov/30971952/
  7. Bell RA, et al. (2009). Diabetes in non-Hispanic white youth: prevalence, incidence, and clinical characteristics: the SEARCH for Diabetes in Youth Study. Diabetes Care 32 Suppl 2(Suppl 2):S102–S111. https://pubmed.ncbi.nlm.nih.gov/19246575/ 
  8. Mayer-Davis EJ, et al. (2018). ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes 19 Suppl 27(Suppl 27):7–19. https://pubmed.ncbi.nlm.nih.gov/30226024/

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