Diabetes Mellitus

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas and the resulting lack of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin. Type 2 DM has a significant association with obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity and is characterized by insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance, as well as relative insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease, 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin replacement is essential in type 1, and a healthy diet, lifestyle changes, and medications are important in type 2.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin or resistance to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin’s action on the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. 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 Bias Epidemiological studies are designed to evaluate a hypothesized relationship between an exposure and an outcome; however, the existence and/or magnitude of these relationships may be erroneously affected by the design and execution of the study itself or by conscious or unconscious errors perpetrated by the investigators or the subjects. These systematic errors are called biases. Types of Biases:
    • 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Gestational diabetes in previous pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • ≥ 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 PCOS Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome)
  • Use of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins leading to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin deficiency
  • HLA-linked (HLA-DQ, HLA-DR3, and HLA-DR4) 
  • Associated with other autoimmune conditions

Type 2

  • Caused by insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance 
  • Relative insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin deficiency
  • Strong family history/genetic component

Gestational diabetes

  • Unclear etiology, but not autoimmune
  • Increased insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion but not sufficient to maintain normal glucose levels
  • Decreased insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance

Maturity onset diabetes of the young

  • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance
  • 14 distinct subtypes 
  • Mechanisms involved:
    • Defective transcriptional regulation
    • Abnormal metabolic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Protein misfolding
    • Dysfunctional ion channels
    • Impaired signal transduction

Pathophysiology

Type 1

  • T-cell immune-mediated destruction of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-producing pancreatic islet cells
  • Autoantibodies (not always detectable):
    • GAD autoantibodies:
      • Target insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-producing pancreatic β cells 
      • Autoimmune destruction of 80%–90% of cells
      • Leads to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin production:
    • Require insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin replacement at all times to treat hyperglycemia 
    • Failure to supplement insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin leads to:
      • Diabetic ketoacidosis Diabetic ketoacidosis Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises ( DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises) (can be life-threatening)
      • Chronic complications of diabetes

Type 2

Type 2 DM is a combination of defective insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion and decreased insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin sensitivity.

  • Defective insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion
  • Peripheral insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance:
    • With constant high intake of glucose, there is a constant high demand for insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
    • Hyperinsulinemia leads to decrease in sensitivity of the insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin receptors in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, muscle, and adipose cells.
    • Down-regulation of receptors leads to vicious cycle of high insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin levels.
  • Additional mechanisms:
    • Impaired hepatic sensitivity to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin leads to lack of inhibition of glycogenolysis and gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
    • Hyperglycemia can impair pancreatic β-cell function and exacerbate insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance.
    • High demand for insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin and excessive production of pancreatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance (similar to type 2)
  • Defect is thought to exist prior to conception; stress from pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care unmasks and worsens it.
  • Effects of maternal hyperglycemia on pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care:
    • Increased risk for preeclampsia
    • Increased risk for birth complicated by shoulder dystocia 
  • Effects of maternal hyperglycemia on developing fetus: 
    • Increased risk for postnatal hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-dependent at presentation
    • Oral medication rapidly loses effect
    • Eventually leads to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin requirement 

Maturity onset diabetes of the young

  • Genetic defects leading to impaired glucose sensing and insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that are transported into the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine by the pancreatic duct. The endocrine function of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas involves the secretion of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin (produced by beta cells) and glucagon (produced by alpha cells) within the pancreatic islets. These 2 hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview 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 DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises:

Type 1 DM often presents urgently with DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises:

  • Usually precipitated by a “tipping” event (e.g., viral illness, trauma, emotional stress)
  • Depressed mental status
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Vomiting
  • Fruity “acetone” breath

Hyperglycemia:

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

  • Polydipsia
  • Polyphagia
  • Polyuria (can present as enuresis Enuresis The elimination disorders that most commonly occur in childhood are enuresis (urinary incontinence) and encopresis (fecal incontinence in inappropriate situations). Enuresis is usually diagnosed when children > 5 years of age continue to wet the bed. Enuresis can occur both in the daytime (diurnal) and at night (nocturnal). Elimination Disorders 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 Hyperosmolar hyperglycemic state Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Hyperosmolar hyperglycemic state occurs due to a relative deficiency of insulin or insulin resistance, leading to severe hyperglycemia and elevated serum osmolality. Hyperglycemic Crises or signs of long-term complications before the diagnosis is known
  • Rarely, DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises present
  • Nonspecific symptoms due to hyperglycemia: 
    • Fatigue
    • Malaise
    • Anorexia
    • Amenorrhea
    • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction
    • Headache
    • Blurred vision 
    • Muscle cramps
    • Dehydration
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin manifestations: 
    • Recurrent cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis or fungal infections
    • Poor or delayed wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing
    • Generalized pruritus
    • Acanthosis nigricans: hyperpigmented velvet-like plaques on the skin of the axilla Axilla The axilla is a pyramid-shaped space located between the upper thorax and the arm. The axilla has a base, an apex, and 4 walls (anterior, medial, lateral, posterior). The base of the pyramid is made up of the axillary skin. The apex is the axillary inlet, located between the 1st rib, superior border of the scapula, and clavicle. Axilla and Brachial Plexus 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-resistant:
    • Distinguishing from type 2 can be challenging
    • Characteristic symptoms of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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
Test Normal range Increasd 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin deficiency (type 1 DM)
    • High levels indicate insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care. 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins positive: helps to identify patients thought to have type 2 DM, but who will likely require insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity or secondary markers of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. 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 Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza, pneumococcal)
  • Regular dental exams

Management

No definitive cure exists for diabetes. Management centers around correcting high blood glucose with insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease or intolerance

Oral medications

 Classes of oral medications used to treat insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin pumps for type 1 diabetes
  • Long-acting insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin: last 12–24 hours
    • NPH NPH Normal pressure hydrocephalus (NPH) is a neurodegenerative disorder characterized by the triad of gait abnormalities, dementia, and urinary urgency or incontinence. Normal pressure hydrocephalus can be either idiopathic or secondary to intraventricular or subarachnoid hemorrhage. Normal Pressure Hydrocephalus (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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin use

The dawn phenomenon:

  • Early in the morning, the effect of exogenous insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin injected the day before disappears.
  • Insulin-antagonistic hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview increase physiologically in the morning.
  • May cause morning hyperglycemia

The Somogyi effect:

  • Rebound morning hyperglycemia
  • Response to hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia during the night after excessive amounts of exogenous insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin the evening before

Complications

Potential complications

Type 1:

  • DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises:
    • Severe hyperglycemia
    • Presents with vomiting, shallow respirations, and confusion
    • Elevation of serum beta-hydroxybutyrate and urine ketones is diagnostic.
    • Can lead to coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma and death if untreated
    • Requires hospitalization
  • Severe insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-induced hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia:
    • Confusion
    • Irritability
    • Anxiety
    • Slurred speech
    • Diplopia
    • Can lead to loss of consciousness, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, or death if untreated
    • Treat with glucagon injection or nasal administration.

Type 2:

  • Hyperosmolar hyperglycemic state ( HHS HHS Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Hyperosmolar hyperglycemic state occurs due to a relative deficiency of insulin or insulin resistance, leading to severe hyperglycemia and elevated serum osmolality. Hyperglycemic Crises): 
    • Severe hyperglycemia results in high osmolarity without significant ketoacidosis. 
    • Symptoms include signs of dehydration, weakness, leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin dose that is too high (overtreatment of hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia)
    • Weight gain worsens insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance and may prompt insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Cesarean Delivery Cesarean delivery (CD) is the operative delivery of ≥ 1 infants through a surgical incision in the maternal abdomen and uterus. Cesarean deliveries may be indicated for a number of either maternal or fetal reasons, most commonly including fetal intolerance to labor, arrest of labor, a history of prior uterine surgery, fetal malpresentation, and placental abnormalities. 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 Coronary heart disease Coronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis. Coronary Heart Disease/acute MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
    • Cerebrovascular disease/stroke
    • Peripheral artery disease Peripheral artery disease Peripheral artery disease (PAD) is obstruction of the arterial lumen resulting in decreased blood flow to the distal limbs. The disease can be a result of atherosclerosis or thrombosis. Patients may be asymptomatic or have progressive claudication, skin discoloration, ischemic ulcers, or gangrene. Peripheral Artery Disease/claudication
  • Microvascular disease: 
    • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
    • Diabetic retinopathy
    • Neuropathy/foot ulcers
  • Fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease

Related videos

Differential Diagnosis

Type 1

  • Maturity onset diabetes of the young (MODY): clinically heterogeneous disorder characterized by non- insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia can occur.
  • Nephrogenic diabetes insipidus Nephrogenic Diabetes Insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). In nephrogenic DI, the kidneys fail to respond to circulating ADH. Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus: form of diabetes insipidus primarily due to kidney pathology. Nephrogenic diabetes insipidus Nephrogenic Diabetes Insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). In nephrogenic DI, the kidneys fail to respond to circulating ADH. Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. 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 Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns, or surgery.

Type 2

  • Metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome: group of conditions including central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. 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 Acromegaly Acromegaly and gigantism are caused by an excessive production of growth hormone (GH) by the pituitary gland. Acromegaly is usually produced by pituitary tumors secreting GH or, less commonly, by extrapituitary disorders. Acromegaly and Gigantism, or glucagon hypersecretion caused by islet alpha cell tumor, Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down Syndrome (trisomy 21), or hemochromatosis, chronic pancreatitis Chronic pancreatitis Chronic pancreatitis is due to persistent inflammation, fibrosis, and irreversible cell damage to the pancreas, resulting in a loss of endocrine and exocrine gland function. The most common etiologies are alcohol abuse and pancreatic duct obstruction. Patients often present with recurrent epigastric abdominal pain, nausea, and features of malabsorption syndrome (diarrhea, steatorrhea, and weight loss). 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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