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Type 1 Diabetes

Image: “Type 1 Diabetes” by BruceBlaus. License: CC BY 3.0


Diabetes Mellitus

Diabetes mellitus (DM) is a chronic systemic disease associated with abnormal carbohydrate, fat, and protein metabolism. It results from insulin deficiency or peripheral tissue resistance to insulin.

Diabetes Subtypes

Type Pathogenesis Acute complications Chronic complications
1 (IDDM)
  • B-cell destruction
  • Immune-mediated or idiopathic
  • Affects non-obese younger patients (< 30 years old)
  • Genetic basis (20–50% twin concordance) with HLA link
Microvascular

Macrovascular

2 (NIDDM)
  • Insulin resistance with relative insulin deficiency initially, progressing to type I diabetes-like pathology
  • Genetic component (60–90% twin concordance)
  • Correlation with obesity
  • DKA precipitated with stress
  • Nonketotic hyperosmolar coma
Microvascular

Macrovascular

Symptoms of Diabetes Mellitus Type 1

Diabetes and High Blood Sugar

Image: ‘Diabetes and High Blood Sugar’ by Bruce Blaus. License: CC BY 3.0

Type-1 diabetes, formerly known as juvenile diabetes, is common in children and young adults. In rare cases, type-1 diabetes occurs in adulthood, which is then known as LADA (latent autoimmune diabetes in the adult).

The pathophysiology of type 1 DM involves autoimmune reaction leading to the destruction of insulin-producing beta cells in the islets of Langerhans of pancreas. The first symptoms of type 1 diabetes appear only after the destruction of 80–90% of the beta cells. Stressful situations can accelerate the disease onset, leading to an acute condition.

As diabetes is only symptomatic when 80–90% of beta cells are destroyed, the onset of the disease is often sudden and dramatic. Noticeable symptoms include weight loss, polydipsia, and polyuria. Due to the absence of insulin hormone, the serum glucose level is greatly elevated as glucose needs insulin to enter the cells. Normally, the kidneys completely reabsorb the filtered glucose, and it is not excreted in the urine. However, as serum glucose concentration rises over 180 mg/dL (10 mmoL/L), the renal threshold is exceeded, and glucose is released into urine via the kidney.

Glucose, being a solvent, when excreted by the kidneys, carries free water with itself. Therefore, these patients suffer from frequent urination (polyuria) and excessive thirst. In young children, this process may lead to enuresis, which is a warning sign of diabetes. Since glucose cannot enter the cells and is processed as an energy source, the body relies on the energy reserves in the fatty tissues, which leads to significant weight loss.

In addition, nonspecific symptoms of the disease, such as malaise, fatigue, anorexia, amenorrhea, impotence and dehydration (exsiccosis) may appear. The consequential harm caused by diabetes is apparent during the subsequent course of the disease. Dry skin, pruritus, muscle cramps, delayed wound healing, and visual disturbances are the first indications of progressive diabetes.

In emergency cases, type 1 diabetes may present with life-threatening metabolic acidosis, known as diabetic ketoacidosis. Due to insulin deficiency, serum glucose cannot be utilized. The fatty acids are then transformed into ketone bodies, which enter the cells independently of insulin and are utilized for energy purposes. However, ketone bodies are acidic in nature, and their excessive accumulation decreases the blood pH, leading to metabolic acidosis.

Patients with diabetic ketoacidosis initially present with nausea, vomiting, dehydration and abdominal pain. Metabolic acidosis may lead to disturbed breathing pattern (Kussmaul breathing), where the patient takes rapid, shallow breaths in order to hyperventilate, which leads to decreased carbon dioxide levels as a compensatory mechanism. Further, the ketone bodies are composed of acetoacetate, β-hydroxybutyrate, and their spontaneous breakdown product, acetone. Therefore, patients presenting with diabetic ketoacidosis may have an acetone-like smell in their breath and urine.

Symptoms of Diabetes Mellitus Type 2

Type 2 DM is most common in adults aged above 40 years. However, due to increased prevalence of obesity in children and adolescents, the younger population is also increasingly diagnosed with type 2 diabetes mellitus. The etiology of type 2 diabetes is multifactorial, with a strong hereditary component. These patients often exhibit metabolic syndrome characterized by central obesity, elevated triglycerides, insulin resistance, and hypertension.

The pathophysiology of type 2 DM involves a combination of peripheral insulin resistance and inadequate insulin secretion by beta cells of the pancreas.

While the onset of type 1 DM is sudden, the progression of type 2 DM is insidious, and is often discovered incidentally during other investigations. Therefore, these patients carry undetected type 2 DM for years and may have developed various microvascular and macrovascular complications, such as visual disturbances, polyneuropathy, chronic renal disease, and impaired wound healing. For this reason, sometimes patients are first diagnosed with type 2 diabetes when they present with these late complications.

Symptoms are nonspecific, similar to those of type 1 diabetes. They include polyuria, polydipsia and polyphagia. Glucosuria may occur when the renal threshold is exceeded due to high serum glucose levels. However, these symptoms are more frequent in type 1 diabetes. Other nonspecific symptoms include:

Diabetic Retinopathy

Image: “Diabetic retinopathy., by Bruce Blaus. License: CC BY 3.0

  • Fatigue, exhaustion

 

  • Concentration problems
  • Headache, dizziness
  • Increased susceptibility to infection (cold, flu)
  • Impaired wound healing
  • Blurred vision
  • Muscle cramps
  • Pruritus
  • Amenorrhea, impotence
  • Frequent infections due to increased sugar content, in particular, in urine (fungi, cystitis, etc.)
  • Acanthosis nigricans
Acanthosis nigricans

Image: “Acanthosis nigricans,” by Madhero88. License: CC BY-SA 3.0

In emergency, patients with type 2 DM may develop hyperosmolar hyperglycemic state (HHS), which is different from diabetic ketoacidosis. In the case of HHS, the serum glucose is markedly elevated, often more than 500 mg/dL, increasing serum osmolarity. These patients often manifest a concomitant illness that leads to reduced fluid intake exacerbating the serum hyperosmolarity. These patients present with features of dehydration, altered sensorium, one or more neurological focal deficits or even coma. The diabetic ketoacidosis is less common in type 2 diabetes than in type 1 diabetes.

Note: Acanthosis nigricans of the inguinal and axillary region is typical seen in young patients with insulin resistance.

Metabolic Syndrome

Elevated waist circumference Men: ≥ 40 inches (102 cm)
Women: ≥ 35 inches (88 cm)
Elevated triglycerides ≥ 150 mg/dL
Reduced HDL (“good”) cholesterol Men: < 40 mg/dL
Women: < 50 mg/dL
Elevated blood pressure ≥ 130/85 mm Hg or use of medication for hypertension
Elevated fasting glucose ≥ 100 mg/dL or use of medication for hyperglycemia
Note: Patients with these findings are generally considered ‘high-risk’ for adverse cardiac events.

Type 1 Versus Type 2 Diabetes

Type 1 Type 2
Weight Normal or thin. Often lose weight prior to diagnosis Overweight or obese
Age Typically first–second decade of life but often occurs at any age as LADA Typically > age 40 years, but can present much earlier
Glycemic patterns Highly variable Less variable
Insulin sensitivity Normal Reduced
Response to oral agents Not responsive Responsive
Antibody status Usually positive Negative
C-peptide level Low or undetectable Detectable or high
Family history First-degree relatives uncommonly affected Strong family history of 1st-degree relatives
Other autoimmune disorders Autoimmune thyroid disease, adrenal insufficiency, vitiligo, and pernicious anemia Absent

Symptoms of Gestational Diabetes

Gestational diabetes is often asymptomatic. Therefore, an oral glucose tolerance test (OGTT) is recommended during the 24th to 28th week of pregnancy. Untreated gestational diabetes can lead to developmental problems in the fetus, which results in increased birth weight (greater than 4 kg requiring a cesarean section), respiratory distress syndrome, hypoglycemia, and hyperbilirubinemia. In emergency cases, the fetus may suffer from diabetic embryopathy.

During pregnancy, due to hydramnios, in which fetus is larger than average, urinary tract infections and preeclampsia can be noticed. Usually, in gestational diabetes, type 2 DM occurs as the hormonal changes lead to insulin resistance in 3–5% of females. In rare cases, pregnancy may trigger type 1 DM.

Symptoms of Diabetes Mellitus Type 3

All the forms of diabetes grouped under type 3 are not easy to diagnose in clinical practice and are often included under type 1 or 2 diabetes based on similar symptoms. The type of diabetes encountered can be established using a specific diagnosis.

Under the world health organization (WHO), all the forms that cannot be considered type 1, 2, or gestational diabetes are grouped into type 3 DM. According to the different etiological factors underlying the rare forms of diabetes, a total of eight groups can be distinguished. Therapeutic measures are similar to those used to manage type 1, 2, and gestational diabetes.

Diabetes due to genetic defects in beta cells of the islets of Langerhans

Maturity onset diabetes of the young (MODY) is caused by genetic defects in glucose metabolism and occurs mainly in adolescence. MODY is attributed to specific gene defects leading to monogenic autosomal dominant disorders. Eleven different forms of MODY have been recognized so far:

  • MODY 1: mutation in chromosome 20, resulting in defective hepatic transcription factor HNF4A
  • MODY 2: mutation in chromosome 7, resulting in defective enzyme glucokinase
  • MODY 3: mutation in chromosome 12, resulting in defective hepatic transcription factor HNF1A
  • MODY 4: mutation in chromosome 13, resulting in defective PDX1
  • MODY 5: mutation in chromosome 17, resulting in defective hepatic transcription factor TCF2
  • MODY 6: mutation in chromosome 2, resulting in defective NEUROD1
  • MODY 7: mutation in chromosome 2, resulting in defective KLF11
  • MODY 8: mutation in chromosome 9, resulting in defective CEL
  • MODY 9: mutation in chromosome 7, resulting in defective PAX4
  • MODY 10: mutation in chromosome 11, resulting in defective INS
  • MODY 11: mutation in chromosome 8, resulting in defective BLK

If MODY is detected early, initial treatment with oral hypoglycemic agents such as sulfonylureas is sufficient. However, it is quite probable that insulin therapy might be necessary.

Diabetes due to genetic defects in insulin action

Two types of diabetes are distinguished based on insulin resistance due to genetic defects. The type A insulin resistance syndrome is characterized by hyperinsulinemia, skin disorders such as acanthosis nigricans (hyperpigmentation and hyperkeratosis (cornification) mostly involving the groin and armpits) and hyperandrogenism in women. Lawrence syndrome or Lipodystrophy is characterized by a massive reduction in subcutaneous fat, which is accompanied by insulin resistance due to previously unknown reasons.

Diabetes as a result of pancreatic disease

All the exocrine pancreatic disorders due to defective pancreas or as a consequence of another disease may lead to diabetes. Such disorders include:

Diabetes due to abnormal hormone synthesis or regulation (endocrinopathy)

Diabetes can accompany the following disorders due to hormonal imbalances:

  • Pheochromocytoma

    Image: “Body scintigraphy 24 hours after intravenous administration of 123Iod-MIBG. Physiological occupancy of the thyroid, liver and bladder. Pathological accumulation in a tumor of the left adrenal glands (pheochromocytoma). Left: from the front. Right: from behind,” by Drahreg01. License: CC BY-SA 3.0

    Acromegaly (abnormal growth hormone somatotropin)

  • Aldosteronoma (elevated aldosterone production)
  • Glucagonoma (tumor related to A-cells of the islets of Langerhans)
  • Hyperthyroidism (overactive thyroid)
  • Cushing’s disease (increased ACTH production)
  • Pheochromocytoma (tumors of the adrenal medulla)
  • Somatostatinoma (tumor of the pancreas or duodenum, with increased somatostatin production)

Diabetes due to drugs or chemicals

Diabetes may occur as an adverse effect of certain drugs and chemicals, including:

  • Alpha interferon (antiviral)
  • Beta-adrenergic agonists (for stimulation of beta receptors in the sympathetic nervous system)
  • Diazoxide (hyperglycemia)
  • Glucocorticoids (against inflammation, overactive immune system, inflammatory rheumatic diseases)
  • Nicotinic acid (to decrease increased blood cholesterol)
  • Pentamidine (antiprotozoal, commonly used in tropical medicine)
  • Phenytoin (for epilepsy, cardiac arrhythmia)
  • Thyroid hormones
  • Thiazide diuretics
  • Vacor (rat poison)

Diabetes due to viral infection

In congenital rubella, caused by the rubella virus, the islet cells of the pancreas may be destroyed resulting in the deficiency of insulin hormone leading to type 1 diabetes. Human cytomegalovirus (CMV) infection also leads to the development of diabetes, as pancreatitis may occur with disease progression.

Diabetes due to immunological defects

In certain autoimmune diseases, such as Stiff-person syndrome (SPS), the endocrine glands may be affected adversely with negative effects on the beta cells of pancreas, resulting in type 1 diabetes. Other immunological defects that trigger type 1 diabetes include the presence of anti-insulin receptor antibodies that block the insulin receptors of the cells.

Diabetes due to genetic disorders

Previously, diabetes was detected as a side effect of numerous genetic syndromes:

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