Diabetes mellitus type 1

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3]Vishal Devarkonda, M.B.B.S[4]Fatemeh Dehghani Firouzabadi, MD [5]

Diabetes mellitus type 1(T1D ) is a metabolic disorder that is primarily characterized by deficiency in insulin. T1D has 2 forms of presentations 1) Classic new onset, which commonly present with persistent thirst, frequent urination, and dehydration 2) Diabetic ketoacidosis, which commonly presents with abdominal pain, vomiting and flu-like symptoms. Patients with classic onset presentation of T1D are usually well appearing. Whereas T1D patients presenting with diabetic ketoacidosis is usually remarkable for tachycardia, tachypnea (kussumal breathing) and dehydration. T1D is characterized by an absolute insulin deficiency. For these patients, a basal-bolus regimen with a long-acting analog and a short- or rapid-acting insulin analog is the most physiologic insulin regimen and the best option for optimal glycemic control.

Term “diabetes” was first described in the literature by a Egyptian scientist Eberes papyrus in 1500 BC. Discovery of insulin by Friedrick Banting in 1921-22, was considered as an important landmark in understanding the nature of disease.

American Diabetic Association(ADA), classifies T1D  based on etiology into 1) Immune mediated and 2) Idiopathic

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels. T1D is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency.

There are no established causes for type 1 DM. Studies have found that cause of T1D is the result of interactions of genetic, environmental, and immunologic factors.

Type 1 DM must be differentiated from type 2 DM, MODY-DM, psychogenic polydipsia, diabetes insipidus, transient hyperglycemia, steroid therapy, renal tubular acidosis type-1, glucagonoma, cushing’s syndrome, and hypothyroidism.

Epidemiology and demographics of type 1 DM varies with geography, age, race and genetic susceptibility.

Risk factors for type 1 DM include family history, genetics, geography, congenital rubella infection, maternal entero-viral infection, cesarean infection, higher birth weight, older maternal age, low maternal intake of vegetables, enteroviral infection, frequent respiratory or enteric infections, early exposure to cereals, root vegetables, eggs and cow’s milk, infant weight gain, persistent or recurrent entero-viral infections, overweight or increased height velocity, high glycemic load, fructose intake, dietary nitrates or nitrosamines, puberty, psychological stress and low vitamin D levels.

According to the American Diabetic Association, screening for type 1 DM is not recommended.^[1]

If left untreated, patients with [type 1 DM] may progress to develop complications of the hyperglycemia state, which commonly include diabetes ketoacidosis and hyperglycemia hyperosmolar state. Prognosis is generally good with compliance with medications.

The diagnosis of type 1 DM is based on the ADA criteria, which include FPG ≥126 mg/dL (7.0 mmol/L), or 2-h PG ≥200 mg/dL (11.1 mmol/L) during an OGTT, or A1C ≥6.5% (48 mmol/mol), or classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).

Type 1 DM has 2 forms of presentations 1) Classic new onset, which commonly present with persistent thirst, frequent urination, and dehydration 2) Diabetic ketoacidosis, which commonly presents with abdominal pain, vomiting and flu-like symptoms.

Patients with classic onset presentation of type 1 DM are usually well appearing. Whereas patients with diabetic ketoacidosis present with tachycardia, tachypnea (kussumal breathing) and dehydration.

Laboratory findings consistent with the diagnosis of type 1 DM include FPG ≥126 mg/dL (7.0 mmol/L), or 2-h PG ≥200 mg/dL (11.1 mmol/L) during an OGTT, or A1C ≥6.5% (48 mmol/mol), or classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).

Type 1 diabetes is characterized by an absolute insulin deficiency. For these patients, a basal-bolus regimen with a long-acting analog and a short- or rapid-acting insulin analog is the most physiologic insulin regimen and the best option for optimal glycemic control.

Surgery is not the first-line treatment option for patients with type 1 DM. β-Cell replacement therapy is usually reserved for patients with either who have an indication for kidney transplantation and are poorly controlled with large glycemic excursions or in patients who already received a kidney transplant.

Currently there are no primary preventive measures available for type 1 DM. However, there are clinical trials ongoing that aim to find methods of preventing or slowing its development.

Secondary prevention strategies following type 1 diabetes mellitus include: maintain optimal glycemic control, life style modifications, and monitoring for micro and macrovascular complications.

Future research mainly focuses of artificial pancreas, beta cell replacement, smart insulin, and gene therapy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]

Term “diabetes” was first described in the literature by a Egyptian scientist Eberes papyrus in 1500 BC. Discovery of insulin by Friedrick Banting in 1921-22, was considered as an important landmark in understanding the nature of disease. In 1970, the autoimmune nature of the type 1 diabetes has been discovered.

• Historically diabetes is an ancient disease, Term diabetes was first described in the literature by Egyptian scientist Eberes papyrus, around 1500 BC.^[1]
• The following are important events in understanding of diabetes history:^{[2][3][4][5][6]}
  • In 1866, Harley reported two distinct forms of disease requiring diametrically opposing form of treatment.
  • In 1921-22, Canadian physician Fredrick Banting and medical student Charles H. Best were credited with discovering the hormone insulin in the pancreatic extracts of dogs.
  • In 1930’s, Harold Himsworth demonstrated the effect of insulin injection in patients who swallowed a simultaneous dose of glucose.
  • In 1951, John Lister concluded that there were two broad groups of diabetics: The young, thin, non-arteriosclerotic group with normal blood pressure and usually an acute onset to the disease and the older, obese, arteriosclerotic group with hypertension and usually an insidious onset.
  • In 1970’s, type 1 diabetes was described as an autoimmune disease in the 1970s, based on observations that autoantibodies against islets were discovered in diabetics with other autoimmune deficiencies.
  • In 1980’s, Immunosuppressive therapies could slow disease progression, further supporting the idea that type 1 diabetes is an autoimmune disorder.
  • In 1996, World Health Organization (WHO) opted for a classification based upon aetiology, and type 1 and type 2 diabetes became the accepted terms.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]Anahita Deylamsalehi, M.D.[3]

According to American Diabetic Association (ADA), type 1 DM could be classified based on both etiology and clinical presentations. Based on etiology type 1 DM can be classified into immune mediated or idiopathic. Nevertheless classic new onset diabetes mellitus and Diabetic ketoacidosis are considered two classes of diabetes mellitus type 1 based on clinical presentations.

• Based on etiology, American diabetic association has classified type 1 DM into:^[1]
  • Immune-mediated
  • Idiopathic
• Based on clinical presentation, Type 1 DM can be classified into:^[2]
  • Classic new onset diabetes mellitus
  • Diabetic ketoacidosis
• Some studies proposed a new subtype of diabetes mellitus type 1. The following are some features of this subtype:^[3][4]
  • There is no relationship to autoimmune conditions, evidenced by absence of any diabetes mellitus type 1 related autoantibodies, such as Glutamate decarboxylase, islet-cell, IA-2, or insulin antibodies.
  • Pancreatic biopsies revealed neither insulitis nor hyperexpression of MHC class I molecules as it is expected in diabetes mellitus type 1. In the contrary lymphocytic infiltrates were reported in the exocrine pancreas.
  • With a rapid onset, only few days after hyperglycemic symptoms (mean duration of four days) patients were diagnosed with diabetic ketoacidosis. The short period of hyperglycemia is evidenced by normal HbA1C in these patients.
  • The study demonstrated that this group has low insulin secretion, which is further supported by a low C-peptide urinary excretion.
  • In contrast to other diabetes mellitus type 1 patients with normal serum pancreatic enzyme concentrations and evidences of insulinitis, this subtype is presented with noticeably elevated pancreatic enzyme level and lymphocytic infiltrates in the exocrine pancreas.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3]Vishal Devarkonda, M.B.B.S[4] Anahita Deylamsalehi, M.D.[5]

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels. Type 1 diabetes is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency. Currently, 58 genomic regions are known to be associated with type 1 DM. There are environmental factors that can play a protective role in Type 1 diabetes like higher maternal vitamin D, probiotic and omega-3 fatty acids intake during prenatal period. Conversely, environmental factors such as caesarean section, congenital rubella, maternal enteroviral infection and abnormal microbiome are among environmental factors that are able to trigger Type 1 DM. Furthermore, some immunological components are responsible for type 1 DM pathogenesis.

• Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels.
• In this form of diabetes, specialized cells in the pancreas called beta cells stop producing insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Lack of insulin results in the inability to use glucose for energy or to control the amount of sugar in the blood.
• Possible thymus and bone marrow deficiency includes defective thymic selection, faulty self antigen presentation, thymic VNTR and Aire expression, mobilopathy and defective lymphocyte precursors are some possible proceeding triggers that underlie type 1 DM.^[1]

• Type 1 DM is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency.
• Concordance of type 1 DM in identical twins ranges between 40 and 60%, indicating the presence of additional modifying factors.
  
  

• Genes associated with Diabetes mellitus include the following: ^{[2][3][4][5][6][7]}
  • Currently, 58 genomic regions are known to be associated with Type 1 DM.
  • Major susceptibility gene for type 1 diabetes is located on HLA region of chromosome 6. It accounts for 40-50% of the genetic risk for type 1 diabetes. This region encodes for class II major histocompatibility complex (MHC) molecules. major histocompatibility complex (MHC) molecules play an important role in presenting antigen to T helper cell and initiating immune response.
  • Other major susceptibility genes which were associated with Type 1 DM include polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, Insulin–VNTR, AIRE, FoxP3, STAT3, HIP14 and PTPN22 etc.^[8][9]
  • Presence of certain genes confer protection against the development of the disease. Haplotype DQA1*0102, DQB1*0602 is extremely rare in individuals with type 1 DM (<1%) and appears to provide protection from type 1 diabetes.
  • There is a relationship between some human leukocyte antigens (HLA) and type 1 diabetes, such as DQB1, DQA1, and DRB1. There are some supporting data on DR4-linked haplotypes transmission from type 2 diabetes parents to offspring with type 1 diabetes. Patients with latent autoimmune diabetes of adults also have been related to HLA alleles DQB1*0302 and 02. ^[9]

• Environmental factors were found to influence Diabetes mellitus type 1 through various pathways. Some were found to confer protection against Diabetes mellitus type 1, while others were associated with the progression and promotion of Diabetes mellitus type 1, including:^[10][11]

• Several studies have found that abnormalities in the humoral and cellular arm of the immune system, were identified to be associated with Diabetes mellitus type 1, these include:^{[12][13][14][15][16][1]}
  • Deficiency in immune regulation, such as effector T cells (Teff) resistance to Regulatory T cells (Treg) or Regulatory T cells (Treg) abnormalities
  • Islet cell autoantibodies
  • Defective cellular trafficking and adhesion
  • Activated lymphocytes in the islets, peripancreatic lymph nodes, and systemic circulation
  • Chronic activation of Antigen-presenting cells
  • T lymphocytes that proliferate when stimulated with islet proteins
  • Release of cytokines within the insulitis
  • An enzyme named glutamic acid decarboxylase (GAD65) found in β cells has similar amino acid sequence with the Coxsackie B4 P2-C protein, which augments the response of humoral immunity.
  • Autoantibodies against IA-2 and zinc transporter (ZnT8) have been positive in 60% and 60-80% of Diabetes mellitus type 1 at the time of diagnose, respectively.

• Conditions associated with diabetes mellitus type 1 include:^[7][17]
  • Autoimmune thyroid disease (ATD)
  • Celiac disease (CD)
  • Autoimmune gastritis (AIG)
  • Pernicious anemia (PA)
  • Vitiligo
  • Addison’s disease
• The following table is a summary of some associated autoimmune conditions and their prevalence among type 1 diabetic patients and normal population.^[18]

• On gross pathology, pancreas may demonstrated the following changes:^[1]
  • Decreased overall weight and size
  • Dorsal region atrophy
  • Possible hypertrophy (related to hydrophic changes)

• On microscopic histopathological analysis, the following changes can be detected in islet cells:^[1]
  • Insulitis
  • Beta cell loss due to necrosis or apoptosis
  • Major histocompatibility complex class one hyperexpression
  • Reduction in insulin in remnant beta cells
  • Interferon alpha expression in beta cells
  • CD3-positive cells in Islet cell

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]

There are no established causes for type 1 diabetes mellitus. Studies have found that cause of type 1 diabetes mellitus is the result of interactions of genetic, environmental, and immunologic factors. There are at least 37 genes associated with type 1 diabetes mellitus. Furthermore, certain infections, diet and some maternal related factors are known to cause type 1 diabetes mellitus.

• The exact cause of type 1 diabetes mellitus remains unknown. Studies have found that cause of type 1 diabetes mellitus is the result of interactions of genetic, environmental, and immunologic factors:^{[1][2][3][4][5][6][7][8][9][10]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Type 1 diabetes mellitus must be differentiated from type 2 diabetes mellitus, maturity onset diabetes of the young (MODY-DM), psychogenic polydipsia, diabetes insipidus, transient hyperglycemia, steroid therapy, renal tubular acidosis type-1, glucagonoma, cushing’s syndrome, and hypothyroidism.

• Differential diagnosis of type 1 diabetes mellitus, include: ^[1][2][3]
  • Type 2 DM
  • MODY-DM
  • Psychogenic polydipsia
  • Diabetes insipidus
  • Transient hyperglycemia
  • Steroid therapy
  • Renal tubular acidosis type-1
  • Glucagonoma
  • Cushing’s syndrome
  • Hypothyroidism
  • Wolfram syndrome
  • Alstrom syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]Anahita Deylamsalehi, M.D.[3]

Epidemiology and demographics of type 1 diabetes mellitus varies with geography, age, race and genetic susceptibility. Incidence of type 1 diabetes mellitus has been increased within the last decade and there are nearly 15-30 million of affected patients around the world. Most type 1 diabetes mellitus patients are children and since it’s incidence dwindles after puberty, only one fourth of patients are diagnosed in their adulthood. The incidence of type 1 diabetes mellitus is related to race and ethnicity of patients. For instance, studies demonstrated that Non-Hispanic white patients have a higher type 1 diabetes mellitus incidence, compared to other races, whereas American Indians had the lowest type 1 diabetes mellitus incidence. Finland has the highest incidence of type 1 diabetes mellitus in the world.

• Incidence of type 1 diabetes mellitus varies with geography, age, race, and genetic susceptibility.
• Epidemiology and demographics of type 1 diabetes mellitus among children:^{[1][2][3][4][5][6][7][8][9][10]}

• At a rate of 3-5% each year since 1960, the incidence of type 1 diabetes mellitus is increasing among children for not fully understood etiologies.^[11] Although it can be interpreted that environmental factors could be at least partially responsible, since genetic factors can not intervene in such a short time.^[12]
• In one study, incidence of type 1 diabetes mellitus in youth of the United States reported 24.3 (95% confidence interval CI, 23.3-25.3).^[13]
• Another study done in Belgium reported an average of 9.9 new cases of diabetes mellitus type 1 per 100,000 individuals per year.^[14]

• Type 1 diabetes affects ~15-30 million people globally.^[1]
• In 2012, Ada estimated the prevalence of type 1 diabetes mellitus in american children and adults at 1.25 million.^[2]
• 5.6% of american adults diagnosed with diabetes mellitus have type 1 diabetes mellitus.^[15]

• The mortality rate among type 1 diabetes mellitus patients was 2.2/1000, based on a study done on Norwegian patients who were diagnosed between 1973 and 1982.^[16]

• Bimodal distribution, with one peak at four to six years of age and a second between 10 to 14 years of age.
• More than 85% of patients with type 1 diabetes mellitus are younger than 20 years old.^[17]
• A study done on European population demonstrated that recent incidence of type 1 diabetes mellitus was highest among individuals younger than 4 years old.^[18] Nevertheless, type 1 diabetes mellitus incidence wanes after puberty.^[17]
• Even though the overall incidence of type 1 diabetes mellitus decreases after puberty, one fourth of individuals with type 1 diabetes mellitus are diagnosed as adults.^[19]

• In one study done on young population of the united states, type 1 diabetes mellitus were reported more frequent among non-Hispanic white, Hispanic and African Americans.^[13]
• The following table is a summary of association between different races and diabetes mellitus type 1 incidence based on various age intervals:^[17]

• Some studies suggest that males are more commonly affected by type 1 diabetes mellitus than females, although non-immunologic subtype of type 1 diabetes mellitus is more common in females.^{[20][[#cite_note-Blohm�Nystr�m1992-21|[21]]][22]} On the other hand, another study suggests that both genders are equally affected.^[23]
• A study of Caucasian population demonstrated male to female ratio of 1.7 among HLA-DR3 associated patients, whereas male to female ratio have been reported 1.0 among HLA-DR4 associated patients.^[24]

• Finland has the highest incidence of type 1 diabetes mellitus in the world.^[25]
• The following is the list of regions which had an increased incidence of type 1 diabetes mellitus from 1990–1999:^[17]
  • Asia
  • Europe
  • North America
• The following is the list of regions which had a decreased incidence of type 1 diabetes mellitus from 1990-1999:^[17]
  • Central American
  • The West Indies
• A study done on Gomel city population with radiation exposure after the Chernobyl incident demonstrated increased incidence of type 1 diabetes mellitus.^[26]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]Anahita Deylamsalehi, M.D.[3]

Risk factors for type 1 Diabetes Mellitus include family history, genetics, geography, congenital rubella infection, cesarean infection, higher birth weight, older maternal age, low maternal intake of vegetables, entero-viral infection, frequent respiratory or enteric infections, early exposure to cereals, root vegetables, eggs and cow’s milk, infant weight gain, persistent or recurrent entero-viral infections, overweight or increased height velocity, high glycemic load, fructose intake, dietary nitrates or nitrosamines, puberty, psychological stress and low vitamin D levels.

• Risk factors for type 1 Diabetes Mellitus include:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]}
  • Family history:
    • There is a risk of developing type 1 diabetes mellitus in close relatives of a patient with type 1 diabetes mellitus.
    • Children who have siblings with type 1 diabetes mellitus started before age of 5 have 3-5 fold higher chance of type 1 diabetes mellitus development before 20 years old, compared to children whose siblings had type 1 diabetes mellitus between 5-15 years old.
    • Offspring of an affected father have 7% chance of type 1 diabetes mellitus, whereas when mother is affected there is only 2% to 3% risk of type 1 diabetes mellitus development in offspring.
  • Genetics: The presence of certain genes associated with an increased risk of developing type 1 diabetes mellitus.
  • Geography: Risk is elevated with increased distance from equator
  • Congenital rubella infection
  • Maternal entero-viral infection
  • Cesarean section
  • Higher birth weight
  • Older maternal age
  • Low maternal intake of vegetables
  • Radiation exposure
    • A study done on Gomel city population with radiation exposure after the Chernobyl incident demonstrated increased incidence of type 1 diabetes mellitus.
  • Enteroviral infection
  • Frequent respiratory or enteric infections
  • Abnormal microbiome
  • Early exposure to cereals, root vegetables, eggs and cow’s milk
  • Infant weight gain
  • Serious life events
  • Persistent or recurrent entero-viral infections
  • Overweight or increased height velocity
  • High glycemic load and fructose intake
  • Dietary nitrates or nitrosamines
  • Puberty
  • Steroid treatment
  • Insulin resistance
  • Psychological stress:
    • There are evidences supporting that normal weighted patients with type 1 diabetes mellitus who experienced moderate to high stress had significantly higher mean blood glucose concentrations, compared to those who reported minimal psychological stress. This relationship could be related to less dietary or therapy adherence in diabetic patients who encountered high stress level.
  • Low vitamin D levels
  • SARS-CoV-2 (a subtype of coronavirus that causes coronavirus disease 2019)
    • Possible β cell damage caused by SARS-CoV-2 can cause to insulin deficiency.
    • Some patients with COVID-19 have been presented with diabetic ketoacidosis (DKA).
  • In one study prevalence of Cannabis use was 30% among type 1 diabetic patients and was related to higher chance of diabetic ketoacidosis (DKA), possibly due to increased intestinal motility and hyperemesis. Nevertheless, further investigations should be done to confirm cannabis use as a risk factor of type 1 diabetes mellitus and DKA.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]Anahita Deylamsalehi, M.D.[3]

According to the American Diabetic Association, screening for diabetes mellitus type 1 is not recommended. Nevertheless, there are some data proposing favorable effects within screened patients.

• According to the American diabetic association screening for diabetes mellitus type 1 is not recommended. However, one should consider referring relatives of those with type 1 diabetes for antibody testing for risk assessment in the setting of a clinical research. Higher-risk individuals may be tested, but only in the context of a clinical research setting.^[1]
• Based on some studies, screening for diabetic patients has some favorable effects. The following table is a summary of screening effects based on 6 pediatric studies:^{[2][3][4][5][6][7]}

_{*TEDDY (The Environmental Determinants of Diabetes in the Young) study reported higher c-peptide level at least within 12 months after diagnosis, which is related to better response to immunologic interventions.^[5]}

_{*DIPP (Finnish Type 1 diabetes Prediction and Prevention) reported lower rate of weight loss among patients who were screened for diabetes mellitus type 1^[8]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]Anahita Deylamsalehi, M.D.[3]

The symptoms of type 1 diabetes usually develop in the first decade of life, and start with non-specific symptoms of classic new onset type 1 diabetes or acute symptoms with diabetic ketoacidosis. If left untreated, patients with type 1 DM may develop acute complications of the hyperglycemia state, such as diabetes ketoacidosis and hyperglycemia hyperosmolar state. In addition other complications related to microvascular or macrovascular changes, such as retinopathy, autonomic neuropathy, dermatology diseases, coronary heart disease, peripheral arterial disease and macular edema. Prognosis is generally good with compliance with medications.

• The symptoms of type 1 diabetes usually develop in the first decade of life, and start with non-specific symptoms of classic new onset type 1 diabetes or acute symptoms with diabetic ketoacidosis. Without treatment, the patient will develop complications of type 1 diabetes.^[1]

• Complications of type 1 diabetes include:^[2][3][4][5]

• In a control study patients with type 1 diabetes had significantly lower total body bone mineral density (BMD) z-score values. Lower levels of osteocalcin, C-terminal telopeptide, calcium, phosphorus, and magnesium have been found in patients with type 1 diabetes, compared to control group.^[6]
• A study demonstrated that children with type 1 diabetes mentioned barriers for physical activity (eg, fear of hypoglycemia, loss of control of diabetes and low fitness). This study report significant improvement with parental support. ^[7]
• Based on a systematic review, type 1 diabetic patients have worse executive function performance, working memory and task switching, compared to the control group.^[8]
• There have been a reported association between early childhood onset of type 1 diabetes mellitus and mild cerebral atrophy and reduced intellectual performance in adulthood.^[9]
• The followings are some related dermatological consequences of type 1 diabetes:^[10]
  • Scleroderma-like skin changes: Pathogenesis is not fully understood, nevertheless advanced glycosylation end products and sugar alcohols buildup in the upper dermis is believed to effect the strengthening of collagen.
  • Cheiroarthropathy (thickened skin and reduced joint mobility)
  • Scleredema diabeticorum
  • Necrobiosis lipoidica
  • Bullosis diabeticorum
  • Xerosis
  • Eruptive xanthomas: Although xanthomas are routinely related to hypertriglyceridemia, type 1 diabetic patients may develop eruptive xanthomas with normal levels of triglyceride. Prevelance of Eruptive xanthomas in type 1 diabetes is approximately 1%.

• Diabetes is a lifelong disease and there is no cure. Tight control of blood glucose can prevent or delay diabetes complications. But these problems can occur, even in people with good diabetes control.^[12]
• When type 1 diabetes mellitus left untreated it can be fatal due to complications like diabetic ketoacidosis.
• Prognosis of type 1 diabetes mellitus is effected by factors such as blood glucose concentration, hemoglobin A1c ([[Glycosylated hemoglobin|HbA1c), lipids, blood pressure, and weight.
• There is a direct relationship between hemoglobin A1c level and long-term cognitive decline.^[13]
• The most common cause of death among type 1 diabetes mellitus patients under 30 years old is acute metabolic complications, based on a study done on Norwegian patients who were diagnosed between 1973 and 1982.^[14]
• The following factors have been related to longer life expectancy in patients with type 1 diabetes:^[15]
  • Proper (not necessarily optimal) glycaemic control
  • High HDL-cholesterol levels
  • Low insulin requirements (insulin sensitive)
  • Normal body mass index (BMI)
  • Proper blood pressure control
  • Patients who do not smoke
  • Absence of microalbuminuria after 15-20 years of type 1 diabetes onset
  • Familial history of long life

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