Diabetes mellitus and COVID-19
Main article: COVID-19
Synonyms and keywords: New-onset Diabetes in COVID-19 New-onset Diabetes Islet cell injury by SARS-CoV 2, COVID-19-associated diabetes mellitus

# Overview
ACE2 receptors in the endocrine pancreas serve the entrance for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), which causes Corononavirus Disease 2019 (COVID-19). Researchers in China observed new-onset diabetes among SARS-CoV patients. Therefore in agreement with this, the SARS-CoV-2 might enter pancreatic islets through binding to ACE2, and cause acute -cell injury, leading to intense hyperglycemia and transient Type 2 Diabetes Mellitus. SARS-CoV 2 can cause hyperglycemia by direct injuring of pancreatic beta cells and by downregulating ACE2 receptors leading to unopposed angiotensin II, which may hinder insulin secretion.According to a recent case report of Diabetic ketoacidoses precipitated by COVID-19 in a patient with newly diagnosed diabetes mellitus, patient was previously healthy presented with a 1-week history of Fever (38.5 C), Vomiting, Polydipsia (intense thirst), and Polyuria (production of abnormally large volumes of dilute urine). He received 6 L of intravenous fluids and intravenous insulin infusion in the initial 24 hours. Diabetic ketoacidosis settled the next day and he was progressed to subcutaneous insulin treatment.
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# Historical Perspective
- Diabetes mellitus is defined by insulin deficiency due to either diminished insulin release or end-organ insulin resistance.
- Diabetes is an umbrella term for conditions such as type I (T1DM) and type II (T2DM) diabetes mellitus, gestational diabetes, and maturity-onset diabetes of the young (MODY).
- Type 1 Diabetes Mellitus is caused by pancreatic -cell failure or auto-immune destruction of the pancreatic -cells. It generally presents in children and young adults.
- Type 2 Diabetes Mellitus (T2DM) is defined by insulin resistance and presents in adults. Family history, hypertension, obesity, and dyslipidemia play a significant role in causing T2DM.
- Around 422 million individuals worldwide have diabetes, the dominant part living in low-and middle-income nations, and 1.6 million deaths are straightforwardly credited to diabetes every year. In the course of recent decades, a consistent rise has been observed in both the incidence and the prevalence.
- In China, in the year 2008, a study was done in which they compared 39 SARS-CoV patients with no previous history of diabetes, who never used steroids, with 39 matched healthy siblings.The results of the study revealed that 20 out of 39 SARS-CoV patients developed new-onset diabetes during the hospital stay. After 3 years of recovery from the SARS-CoV infection, only 5% of patients remained diabetic whereas blood sugar levels normalized in the rest of the patients with the infection recovery.
- ACE2 is the primary receptor For SARS-CoV spike protein. SARS-CoV causes infection by binding to ACE2 receptors on the target cells. The study suggested, SARS-CoV may damage islets and cause acute insulin dependent diabetes mellitus.
- In mid-April 2020, Finn Gnadt, an 18-year-old student from Kiel, Germany, learnt that he had been infected with the SARS-CoV-2 coronavirus.
- Gnadt thought he had endured the infection unscathed, but days later, he started to feel worn out and exceedingly thirsty. In early May, he was diagnosed with type 1 diabetes, and his physician, Tim Hollstein at the University Hospital Schleswig-Holstein in Kiel, suggested that the sudden onset might be linked to the viral infection.
- Hollstein suspected that the virus had destroyed his -cells because his blood didnt contain the types of immune cells that typically damage the pancreatic islets where the -cells live.
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# Classification
- There is no established system for the classification of COVID-19-associated Diabetes.
- Future research is needed to provide a better understanding of the type of Diabetes, SARS-CoV-2 can cause. Whether SARS-CoV-2 causes T1DM or T2DM or a new type of Diabetes.
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# Pathophysiology
- Angiotensin-converting enzyme 2 (ACE2) receptors expressed in the tissues that are highly involved in body metabolism. These tissues comprise of pancreatic beta cells, adipose tissue, small intestine, and the kidneys. ACE2 receptors in the endocrine pancreas serve the entrance for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), which causes Corononavirus Disease 2019 (COVID-19). 
- Expression of ACE2 receptors and  effector protease TMPRSS2 in pancreas are associated with SARS-CoV 2 infection.
- The pancreas consists of nine different cell types such as acinar cells, ductal cells, beta cells, alpha cells, mesenchymal cells, and endothelial cells. These pancreatic cells express both ACE2 and TMPRSS2. The expression of ACE2 in pancreatic alpha and beta cells is further proved by immunohistochemistry. Both beta cells that secrete insulin and alpha cells that secrete glucagon, stained positive for SARS-CoV 2 Spike protein and thus, it is postulated that SARS-CoV-2 can infect pancreatic islet cells.
- A recent experiement was conducted to study SARS-CoV-2 tropism that is the cellular response to an external stimulus in human cells and organoids. Researchers infect human pluripotent stem cells (hPSC)-derived pancreatic endocrine cells with SARS-CoV-2.
- Researchers found when SARS-CoV-2 infect pancreatic cells, it downregulates the pathways including calcium signaling pathways, glucagon signaling pathways of alpha cells, and metabolic pathways that assist in insulin secretion from pancreatic beta cells.
- Researchers further stained SARS-CoV-2 infected hPSC-derived pancreatic endocrine cells with a cell apoptotic marker (CASP3). As a result of this staining, they found a large number of CASP3 cells in infected hPSC-derived pancreatic cells. This indicates that change in metabolic pathways of the pancreas is mainly due to cell apoptosis, trigger by SARS-CoV-2. This experiment suggest that when SARS-CoV-2 binds to ACE2 in pancreas, this will upregulate the genes responsible for apoptosis and downregulate the genes responsible for the cell survival. 
- ACE2 is the target receptor for both SARS-CoV and SARS-CoV-2. Researchers in China observed new-onset diabetes among SARS-CoV patients. Therefore in agreement with this, the SARS-CoV-2 might enter pancreatic islets through binding to ACE2, and cause acute -cell injury, leading to intense hyperglycemia and transient Type 2 Diabetes Mellitus.
- ACE2 serves as the negative regulator of the Renin-Angiotensin System (RAS) mainly by converting Ang (angiotensin) I and Ang II into Ang 1-9 and Ang 1-7, respectively. When SARS-CoV and SARS-CoV-2 bind to ACE2 receptors, this will lead to the subsequent downregulation of surface ACE2 expression. SARS-CoV-2 differs from SARS-CoV by 380 amino acid substitutions and thus has a stronger binding affinity than SARS-CoV, which explains the global impact of SARS-CoV-2 than the previous SARS-CoV outbreak.
- ACE2 is the negative regulator of the Renin-Angiotensin system (RAS) and has protective benefits against many diseases and complications. SARS-CoV-2 binds to ACE2 receptors, this blocks all the protective benefits of the ACE2 pathway and shifts the cascade back to ACE/Ang II/AT1R-pathway, increasing Ang II, decreasing ACE2 and Ang-( 1-7) as shown in the figure.
- Inhibition of RAS(AngiotensinAng1Ang2AT1R) protects pancreatic -cells from oxidative stress-related tissue damage, therefore improves insulin synthesis and secretion.Hyperactivity of RAS works in contrast. In adipose tissue, Ras decreases insulin sensitivity, decreases glucose uptake. In pancreatic tissue, it decreases insulin secretion, increases islet oxidative stress and fibrosis, decrease perfusion.
- In an experimental trial, pressor doses of Ang-II were given to healthy human subjects. As a result, researchers observed suppression of basal, pulsatile, and glucose-stimulated insulin release.This loss of insulin release is supposed to be the contributing factor in the development of T2DM.
- SARS-CoV 2 can cause hyperglycemia by direct injuring of pancreatic beta cells and by downregulating ACE2 receptors leading to unopposed angiotensin II, which may hinder insulin secretion.
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# Causes
- SARS-CoV-2 can cause COVID-19-associated diabetes mellitus by two mechanisms:
- Direst damage of pancreatic beta-cells by SARS-CoV 2 
- Downregulation of ACE2 by SARS-CoV 2 shift the cascade to the ACE/AngII/AT1R pathway which further leads to decrease insulin release and islet cell oxidative damage.
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# Differentiating COVID-19-associated diabetes mellitus from other Diseases
- For more information on COVID-19-associated diabetes mellitus differential diagnosis click here.
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# Epidemiology and Demographics
- There is not enough data available on incidence and prevalence of COVID-19-associated Diabetes Mellitus.
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# Risk Factors
- There are no established risk factors for COVID-19-associated Diabetes.
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# Screening
- There is insufficient evidence to recommend routine screening for COVID-19-associated Diabetes.
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# Natural History, Complications, and Prognosis

## Natural History
- A high blood sugar level can present with several symptoms, including:
- Blurry vision
- Excess thirst
- Fatigue
- Frequent urination
- Hunger
- Weight loss

## Complications
- After many years, high blood sugar can lead to serious complications:
- Blindness
- Infection:As a result of high blood sugar, feet and skin can develop sores and infections.
- High blood pressure and cholesterol: Diabetes may make it harder to control blood pressure and cholesterol. This can lead to a heart attack, stroke, and other problems. It can become harder for blood to flow to legs and feet.
- Neuropathy: High blood sugar can damage the nerves, causing pain, tingling, and numbness.
- Nephropathy: High blood sugar and other problems can lead to kidney damage. Kidneys may not work as well as they used to. They may even stop working so that one needs dialysis or a kidney transplant.
- Immune Dysfunction: Immune system can weaken, which can lead to frequent infections.

## Prognosis
- There is not enough data available on the prognosis of SARS-CoV-2 induced Diabetes Mellitus. Based on the data of SARS-CoV induced diabetes, the overall prognosis is good.
- In China, in the year 2008, a study was done in which they compared 39 SARS-CoV patients with no previous history of diabetes, who never used steroids, with 39 matched healthy siblings. The results of the study revealed that 20 out of 39 SARS-CoV patients developed new-onset diabetes during the hospital stay. After 3 years of recovery from the SARS-CoV infection, only 5% of patients remained diabetic whereas blood sugar levels normalized in the rest of the patients with the infection recovery.
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# Diagnosis

## Diagnostic Study of Choice
- Diagnostic study of choice for diabetes mellitus is fasting plasma glucose (FPG). According to the American Diabetes Association (ADA) criteria, diabetes mellitus is diagnosed with FPG 126 mg/dL (7.0 mmol/L). 
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## History and Symptoms
- According to a recent case report of Diabetic ketoacidoses precipitated by COVID-19 in a patient with newly diagnosed diabetes mellitus. He was a previously healthy man presented with 1-week history of:
Fever (38.5 C)
Vomiting,
Polydipsia (intense thirst)
Polyuria (production of abnormally large volumes of dilute urine)
- Fever (38.5 C)
- Vomiting,
- Polydipsia (intense thirst)
- Polyuria (production of abnormally large volumes of dilute urine)
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## Physical Examination
- Mildly tachycardic
- Kusmmaul's breathing was not observed.
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## Laboratory Findings
- COVID-19 infection can cause ketosis and ketoacidosis.When the body doesnt make enough insulin to break down sugar, it uses ketones as an alternative source of fuel.
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## Electrocardiogram
- There are no electrocardiographic findings of COVID-19 associated Diabetes Mellitus.
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## X-ray
- There are no X-ray findings of COVID-19-associated diabetes mellitus.
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## Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with COVID-19-associated diabetes mellitus.
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## CT Scan
- There are no CT scan findings associated with COVID-19-associated diabetes mellitus.
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## MRI
- There are no MRI findings associated with COVID-19-associated diabetes mellitus.
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## Other Diagnostic Studies
- Fasting plasma glucose (FPG) test
- HbA1C or A1C test
- Random plasma glucose (RPG) test

# Treatment

## Medical Therapy
- A 37-year-old, already healthy man determined to have COVID-19-associated diabetes mellitus. The patient got 6 L of intravenous fluids and intravenous insulin infusion in the initial 24 hours. Diabetic ketoacidosis settled the next day and he was progressed to subcutaneous insulin treatment.
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## Surgery
- Surgical intervention is not recommended for the management of COVID-19-associated diabetes mellitus.
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## Primary Prevention
- Keeping an ideal body weight and an active lifestyle may prevent or delay the start of diabetes. If overweight, losing just 5% of body weight can reduce the risk.
- There have been rigorous efforts in order to develop a vaccine for novel coronavirus and several vaccines are in the later phases of trials.
- The best way to prevent infection is to avoid being exposed to this virus. CDC recommends following practices that should be adopted for infection control:
Hand washing often with soap and water for at least 20 seconds.
Using an alcohol-based hand sanitizer that contains at least 60% alcohol if soap and water are not available.
Staying at least 6 feet (about 2 arms length) from other people who do not live with you.
Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs.
Cleaning and disinfecting.
- Hand washing often with soap and water for at least 20 seconds.
- Using an alcohol-based hand sanitizer that contains at least 60% alcohol if soap and water are not available.
- Staying at least 6 feet (about 2 arms length) from other people who do not live with you.
- Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs.
- Cleaning and disinfecting.
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## Secondary Prevention
- Getting better control over your blood sugar, cholesterol, and blood pressure levels help reduce the risk for kidney disease, eye disease, nervous system disease, heart attack, and stroke.
- WHO recommends home care for patients with suspected COVID-19 who present with mild symptoms.
- It is highly recommended for people with suspected or affirmed COVID-19 (including those anticipating test results) should remain at home and attempt to isolate themselves from other members and animals in the family unit.
- World Health Organization (WHO) has recommended wearing a medical mask if family members are in the same room with the COVID-19 patient to prevent the spread of the virus. Whereas, according to the United States Centers for Disease Control and Prevention (CDC), a cloth face Cover can be acceptable for caregivers at home and has considered the use of a medical mask for healthcare workers.
- It is highly recommended for COVID-19 patients to use a separate bedroom and bathroom to prevent the spread of infection to family members. To avoid sharing rooms and if sharing space in a home is unavoidable, keeping a six feet (two meters) distance is extremely emphasized. Care providers should perform hand hygiene after any form of contact with patients or their immediate environment. In a process of providing care to the patient, the caregiver should wear gloves while touching the patient's blood, stool, or body fluids, such as saliva, sputum, nasal mucus, vomit, and urine. Certain things should not be shared with COVID-19 patients such as dishes, drinking glasses, cups, eating utensils, towels, bedding, and thermometers. After the COVID-19 patients use these things, they should be properly disinfected.
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