Covid-19 and the onset of diabetes: a clinical case that challenges
This is the story of a 19-year-old German who presents to the hospital emergency room with diabetic ketoacidosis, a serious complication of diabetes. This clinical case was published online September 2, 2020 in the journal Nature Metabolism .
The young man is unusually tired, exhausted and has lost 12 pounds in the previous weeks. He is excessively thirsty leading to the consumption of very abundant drinks (about 6 liters per day) and must get up at night to urinate. In addition to polydipsia and nocturia, there is intermittent pain in the left flank after meals. The young patient does not have a fever. Five to seven weeks earlier, he presented with an asymptomatic SARS-CoV-2 infection, acquired during a stay in Austria with his family.
Blood tests reveal diabetic ketoacidosis , an acute metabolic complication of diabetes mainly seen in type 1 diabetes and which is manifested in particular by abdominal pain.
Diabetic ketoacidosis occurs when insulin levels are insufficient to meet basic metabolic needs. When there is not enough insulin, most cells cannot use the glucose in the blood. They then go about it differently to obtain energy, in this case by going to the cells of the adipose tissue. By breaking down triglycerides (lipids), cells release compounds called ketones (or ketone bodies) which then provide them with the necessary energy. This process (ketosis) is accompanied at the same time by an excess of acidity in the blood, which results in a drop in blood pH (acidosis). It is this metabolic state, characterized by the accumulation of ketone bodies in the blood with increased acidity, that we call diabetic ketoacidosis.
Genetically, the young patient carries a tissue group (HLA DR1-DR3-DQ2) which predisposes him only to a slight increase in the risk of developing autoimmune type 1 diabetes.
Absence of antibodies classically associated with insulin-dependent diabetes
Above all, the young man does not present, as is the case in type 1 diabetes, autoimmunity markers associated with this condition. Thus, immunological analyzes do not detect the presence of antibodies directed against the beta (β) cells of the pancreatic islets (which synthesize and secrete insulin), the enzymes glutamate decarboxylase 65 (GAD65) and tyrosine phosphatase (which acts on the insulin receptor and allows this hormone to exert its action at the cellular level), the insulin itself and the zinc transporter ZnT8 (protein present on the membrane of the secretory granules of pancreatic beta cells).
The young patient therefore presented, after infection with SARS-CoV-2, insulin-dependent diabetes in the absence of autoantibodies, a situation which has already been described and which would not be rare.
But let’s go back to the weeks leading up to his emergency admission for diabetic ketoacidosis at the university hospital in Kiel (Land of Schleswig-Holstein). It all starts on March 14, 2020, when the family returns from a stay in Austria. Two days later, on March 16, both parents showed typical symptoms of Covid-19, namely a dry cough, chills, fatigue, respiratory discomfort, joint pain, loss of smell and taste. PCR diagnostic tests are not performed because at that time the health authorities did not recommend them in this context.
On April 6, their 19-year-old son presented symptoms suggestive of diabetes, namely fatigue, polydipsia-polyuria (feeling of intense thirst with increased urine volume) worsening over time. . The young man does not, however, develop symptoms typical of Covid-19. Four days later, on April 20, he realized that he had lost a lot of weight. At the same time, her parents are recovering from their symptoms.
On April 29, 2020, the young man is, like his two parents, tested positive for SARS-CoV-2. The PCR test is negative for his twin brother who does not present signs suggestive of Covid-19 or diabetes.
In the young patient, blood tests show the presence of anti-SARS-CoV-2 IgG antibodies, but no IgM antibodies, which indicates that the Covid-19 disease is not recent. Indeed, the presence of IgM antibodies indicates a recently acquired infection, these being detected in the blood up to four weeks after infection with SARS-CoV-2.
We know the rest. On May 5, the young patient presented to the emergency room of the Kiel University Hospital Center because his clinical condition had deteriorated. Doctors then diagnose insulin-dependent diabetes.
Doctors thus estimate that the period during which the young patient was infected with SARS-CoV-2 corresponds to the last two weeks of March 2020 insofar as it is unlikely that he developed Covid-19 during April of fact of the absence of IgM antibodies directed against SARS-CoV-2.
After having excluded, in view of the clinical signs and the results of laboratory tests, the diagnosis of acute pancreatitis, the young patient is admitted to the intensive care unit where he receives insulin by intravenous route. Four days later, he was transferred to the endocrinology department with a switch from insulin therapy to the subcutaneous route, his clinical condition improving. His blood sugar then stabilizes at 8.4-10.2 mmol / L, or 1.51 to 1.83 g / L (normal values: 0.70g / L-1.10g / L). The young man leaves the hospital ten days later.
Several weeks after infection with the SARS-CoV-2 coronavirus, this patient therefore presented with severe ketoacidosis, testifying to a loss of function of the pancreatic β cells that secrete insulin.
The ACE2 receptor is expressed by insulin-secreting cells
Recent studies have shown that the ACE2 protein, which serves as the cellular gateway for SARS-CoV-2, is expressed by adult human beta cells (as well as alpha cells which secrete the hormone glucagon which, in the reverse of insulin, increases the level of glucose in the blood). “Given that ACE2 is expressed on β cells of the human pancreas and is the primary receptor for SARS-CoV-2, we believe that in this patient direct cytolytic β cell damage due to SARS-CoV-2 infection resulted in insulin-dependent diabetes in the absence of obvious classic autoimmune pathology, ” state Matthias Laudes and colleagues.
And the researchers add that a study published last July in the journal Cell Stem Cell showed that infection with SARS-CoV-2 of endocrine (hormone-secreting) cells in pancreatic tissue is accompanied by increased production of chemokines  (molecules produced by immune cells), similar to that found in autopsy samples from patients with Covid-19.
The German authors therefore believe that “Covid-19 could have led to type 1 diabetes in our patient” , while stressing that the causal link between the viral infection and the diabetic pathology cannot be formally established and that studies are needed to better determine the direct effect of SARS-CoV-2 on pancreatic islet cells .
This observation is in addition to other recently published cases of patients who developed ketoacidosis promoted by Covid-19.
We know that diabetes is considered a risk factor for progression to severe and critical forms of Covid-19. Future studies and the establishment of an international registry  should therefore focus on determining whether the SARS-CoV-2 infection is diabetogenic, in other words whether Covid-19 influences the mechanisms and evolution of diabetic disease in patients already suffering from diabetes but also in what proportion this viral infection can lead to the occurrence of diabetes and what type of diabetes.
According to the authors, this clinical case seems to illustrate, once again, that Covid-19 is a disease with many faces , in other words a systemic pathology insofar as it affects several organs and tissues. He concluded that “diabetologists should be aware of the possibility of the occurrence of insulin-dependent diabetes as an acute complication in patients infected with SARS-CoV-2”.
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 The biological blood and urine analyzes show a blood pH of 7.1, a glycemia at 30.6 mmol / L (5.52 g / L), a drop in the serum concentration of C peptide to 0.62 μg / L (normal values: 1.1–4.4 μg / L) and a glycated hemoglobin (HbA1c) level of 16.8%, as well as ketonuria (presence of ketone bodies in the urine) and glycosuria (presence of glucose in the urine). The authors point out that one might think that their patient’s elevated HbA1c level at the time of diagnosis does not argue for the recent occurrence of type 1 diabetes due to Covid-19. However, they point out that although an elevated HbA1c level may suggest the existence of hyperglycemia for several weeks, cases of diabetic ketoacidosis with very high HbA1c levels, regardless of the duration of the diabetes, have been reported in several studies. He added that we know that variations in the survival of red blood cells can lead to variations in the level of HbA1c for a given average blood sugar level. According to the authors, these studies indicate that the markedly elevated HbA1c level in this patient therefore does not exclude the recent occurrence of type 1 diabetes within the time periods indicated.
 This study used pancreatic endocrine cells generated from human pluripotent stem cells (hPSC). After infection with SARS-CoV-2, it showed a robust production of the chemokines CCL2, CXCL5 and CXCL6 as well as markers of apoptosis (cell death). Researchers have also shown that SARS-CoV-2 infects in vitro cells making up pancreatic organoids (miniature organs obtained from hPSC, but devoid of immune cells) previously transplanted into humanized mice.
 Studies have shown that viral infections seem to play a role in the occurrence of type 1 diabetes, such as enteroviruses (especially Coxsackievirus B), but also rotaviruses, the mumps virus (responsible for mumps) , cytomegalovirus.
 A global registry of diabetes associated with Covid-19 has been launched (Global Registry of COVID-19-related diabetes, covidiab.e-dendrite.com ). Likewise, a long-term follow-up study (COVIDOM) is being conducted by the University Hospital of Schleswig-Holstein (Kiel) with Covid-19 patients.