Long-term Effects of Covid-19 İnfection and Pandemic Period in Patients with Type 2 Diabetes Mellitus

1. Introduction

Covid19 is a disease caused by the SARS-CoV2 virus, a new member of the coronavirus family. It was first detected in Wuhan in 2019, then spread worldwide and caused a pandemic [1]. It has a more severe course and higher mortality in patients who are elderly and have comorbid diseases such as diabetes. COVID-19 patients with diabetes have a higher rate of hospital admission, hospitalization, development of severe pneumonia, and mortality [2]. The main reasons for the more severe course of infectious diseases in diabetic patients include chronic inflammation, a tendency to cellular attachment, impaired T lymphocyte cell functions, decreased virus clearance, uncontrolled hyperinflammation and predisposition to cytokine storm that may develop [3,4].

It is thought that in COVID-19 infection, the virus attaches to the cells containing its receptor and enters the cell, causing damage [5]. Receptors are found in many systems, organs, and cells. These receptors have also been shown in pancreatic islet cells [6]. It is thought that severe infection may cause pancreatic damage, resulting in a decrease in pancreatic reserve and impaired regulation in diabetic patients.

Our study aimed to examine the effects of severe COVID-19 infection on metabolic parameters and blood sugar regulation in diabetic patients in the medium and long term.

2. Materials and Methods

Study Design

The study is a retrospective cohort study conducted to investigate the effect of COVID-19 infection on patients with type 2 diabetes. Two groups of patients selected from patients who were admitted to internal medicine or endocrinology and metabolism outpatient clinics between 01/02/2021 - 01/05/2021, were hospitalized due to COVID-19 infection between 01/04/2020 - 01/07/2020 (Group 1) and did not have COVID-19 infection during this period (Group 2) were included in the study. The changes in control diabetes and other metabolic parameters of the patients after six months were compared as inter- and intra-group, and the differences between the groups were examined.

Ethical approval and Declaration

Approval was obtained from Kütahya University of Health Sciences, Faculty of Medicine, Non-Interventional Research Ethics Committee on 09.02.2022 with decision number 2022/02-13 before the study. The study was conducted in accordance with the latest version of the "Declaration of Helsinki" and the "Good Clinical Practice Directive".

Study Population

A total of 127 patients, including 79 women and 48 men, were included in the study; 64 of these patients had Covid-19 and 63 had no infection.

Inclusion criteria were defined as being a patient over 18 years of age and diagnosed with type 2 diabetes mellitus. Patients who were younger than 18 years of age, had active malignancy, developed diabetes after pancreatic surgery, had chronic liver disease, and chronic alcohol use were excluded from the study.

The patient group included diabetic patients who had COVID-19 during the first three months of the pandemic and then came to routine outpatient clinic control for diabetes. The control group included patients with type 2 diabetes over the age of 18 who did not have COVID-19 infection and were admitted to the outpatient clinic for diabetes control.

Laboratory Parameters

HbA1c, fasting plasma glucose (FPG), lipid profile (LDL, HDL, triglyceride, total cholesterol), ALT, creatinine, uric acid, TSH, amylase, and lipase were recorded retrospectively. The results of the patient's samples were analyzed at the Central Laboratory of Kütahya Health Sciences University Evliya Çelebi Training and Research Hospital.

Age, gender, smoking history, height, body weight, duration of diabetes mellitus, medications, and comorbidities were recorded by analyzing the patient files.

HbA1C levels were measured immediately after blood samples were taken without waiting. Measurements were performed by high-pressure liquid chromatography (HPLC) with a Tosoh G8 HPLC Analyser (TosohBioscience, Inc., San Francisco, CA). Fasting blood glucose and lipid parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides) were measured on the day blood samples were taken without waiting. APG and lipid panels were measured with the original kits using a BeckmanCoulter AU680 instrument (BeckmanCoulter, Miami, FL, USA). The reference ranges of biochemical parameters were as follows: FPG 74-106 mg/dL, total cholesterol <200 mg/dl, HDL-cholesterol>40 mg/dL, LDL-cholesterol <100 mg/dl, and triglyceride<150 mg/dl.

Statistical Analysis

SPSS (Statistical Package for SocialScience) version 22 program was used to analyze the study data. The suitability of continuous variables to normal distribution was examined with Kolmogorov-Smirnov and Shapiro-Wilk tests. Normally distributed data were expressed as mean±standard deviation, non-normally distributed data were expressed as median and interquartile range (25-75 percent), and categorical variables were expressed as percentages. Differences between independent groups were compared using the Student t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data. Categorical parameters were analyzed using the Chi-square test. In the correlation analysis, the Pearson correlation test was used for variables with normal distribution, and Spearman's correlation test was used for variables that did not show normal distribution. For all tests, a p-value of < 0.05 was considered statistically significant.

3. Results

Considering the demographic characteristics of all patients, it is seen that there are a total of 127 participants, 79 women and 48 men. 62% of the participants are women and 37.8% are men. There is no statistically significant difference between patient groups and gender (p>0.05). The mean age of patients who had Covid 19 was 58.09 years and the standard deviation was 9.736. The average age of patients who did not have Covid 19 was 54.33 and the standard deviation was 10.799. There is a statistically significant correlation between patient groups and age (p<0.05). No statistically significant difference was detected between BMI and duration of diabetes in the patient groups (p>0.05) (Table 1).

When the common data of all patients was examined, no statistically significant difference was detected in FPG and triglyceride values at baseline and control (p>0.05). A significant difference was detected in HbA1c, total cholesterol, LDL cholesterol, and HDL cholesterol values (p<0.05). While the HbA1c value was found to be lower in the control, cholesterol values (total cholesterol, LDL cholesterol, HDL cholesterol) were found to be higher (Table 3).

The intragroups evaluation is given in Table 4. In group 1, HbA1c value was found to be statistically significantly lower, and cholesterol values (total cholesterol, LDL cholesterol, HDL cholesterol) were found to be higher (p<0.05). It was observed that HbA1c decreased from 8 to 7.7, total cholesterol increased from 193.11 to 216.13, LDL cholesterol increased from 113.7 to 124.9, and HDL cholesterol increased from 42.9 to 52.3. In Group 2, a significant difference was detected only in HbA1c and HDL cholesterol values (p<0.05). It was observed that HbA1c decreased from 7.9 to 6.9 and HDL cholesterol increased from 48.5 to 51.8. No significant difference was detected in other values (FPG, Total cholesterol, LDL cholesterol, Triglyceride) (p>0.05).

Table 4.1. Change in diabetes control and cholesterol panel in group 1 during 6 months.

	Group 1
	First control			Control after 6 months
	Average	Median	st deviation	Average	Median	st deviation	p-value
APG	158.7	142.00	65.047	158.66	134.50	67.557	0.952
HbA1c	8.044	7.600	1.796	7.74	7.100	1.855	0.003
T.cholesterol	193.11	183.00	69.328	216.13	212.50	46.472	.000
LDL	113.7	111.500	53.534	124.93	124.00	34.296	0.003
HDL	42.96	40.50	15.944	52.3	51.50	11.625	.000
Triglycerides	199.5	157.00	170.697	196.44	175.50	99.812	0.355

Table 4.1. Change in diabetes control and cholesterol panel in group 1 during 6 months.

	Group 1
	First control			Control after 6 months
	Average	Median	st deviation	Average	Median	st deviation	p-value
APG	158.7	142.00	65.047	158.66	134.50	67.557	0.952
HbA1c	8.044	7.600	1.796	7.74	7.100	1.855	0.003
T.cholesterol	193.11	183.00	69.328	216.13	212.50	46.472	.000
LDL	113.7	111.500	53.534	124.93	124.00	34.296	0.003
HDL	42.96	40.50	15.944	52.3	51.50	11.625	.000
Triglycerides	199.5	157.00	170.697	196.44	175.50	99.812	0.355

Table 4.2. Change in diabetes control and cholesterol panel in group 2 during 6 months.

	Group 2
	First control			Control after 6 months
	Average	Median	st deviation	Average	Median	st deviation	p-value
APG	149.66	142.00	48.712	152.85	139.00	69.827	0.12
HbA1c	7.961	7.100	69.827	7.621	6.900	2.572	0.043
T.cholesterol	199.1	202.00	49.618	200.16	201.00	49.087	0.492
LDL	116.878	117.00	41.881	117.71	122.00	41.191	0.804
HDL	48.52	48.00	12.921	51.84	49.00	13.409	0.001
Triglycerides	182.02	159.00	96.621	187.02	151.00	119.503	0.76

Table 4.2. Change in diabetes control and cholesterol panel in group 2 during 6 months.

	Group 2
	First control			Control after 6 months
	Average	Median	st deviation	Average	Median	st deviation	p-value
APG	149.66	142.00	48.712	152.85	139.00	69.827	0.12
HbA1c	7.961	7.100	69.827	7.621	6.900	2.572	0.043
T.cholesterol	199.1	202.00	49.618	200.16	201.00	49.087	0.492
LDL	116.878	117.00	41.881	117.71	122.00	41.191	0.804
HDL	48.52	48.00	12.921	51.84	49.00	13.409	0.001
Triglycerides	182.02	159.00	96.621	187.02	151.00	119.503	0.76

Insulin, c-peptide, and urine albumin levels were measured in all patients at follow-up to evaluate pancreatic reserve and the presence of nephropathy. No significant difference was detected in insulin, c-peptide, and spot urine albumin values between the groups (p>0.05) (Table 5).

4. Discussion

In this study, we retrospectively analyzed the effects of the pandemic period and the disease on metabolic parameters in diabetic patients with COVID-19 infection. Our findings show that diabetic patients with COVID-19 infection do not have a significant deterioration in blood glucose regulation in the long term, but there is a significant increase in the cholesterol panel (total cholesterol and LDL cholesterol).

Diabetes has become an increasing health problem today. Individuals with diabetes are more vulnerable to infectious diseases, and these diseases generally have a more severe course. COVID-19 infection also confirms this situation. Type 2 DM patients have a high risk of developing severe COVID-19, and it is also known that the incidence of severe acute metabolic complications of diabetes, such as the development of new-onset diabetes, dysregulation, or diabetic ketoacidosis due to COVID-19, is increased [7-9]. Additionally, COVID-19 tends to be more severe in individuals with diabetes [10]. A study reported that 30-40% of patients hospitalized due to COVID-19, who required intensive care, and experienced mortality, had a diagnosis of diabetes [11]. However, information about the effect of diabetes control in the medium and long term after COVID-19 infection is not clear. It is known that the SARS-CoV-2 virus enters cells via the ACE-2 receptor, causing cellular damage. This mechanism can also damage pancreatic islet cells, potentially leading to pancreatitis [12]. In a study by Chen J et al, it was reported that no significant change was found in HbA1c values of diabetic patients after COVID-19 infection [13]. In our study, it was determined that there was no deterioration in diabetes regulation in the medium term in patients who had moderate or severe COVID-19 and received inpatient treatment in the hospital, on the contrary, there was an improvement. The reason for this was thought to be that blood glucose regulation was provided with close follow-up and treatment during hospitalization, and blood glucose levels approached the target values with short interval controls in the post-infection period.

The impact of restrictions implemented during the pandemic on diabetes control is another topic of debate. In the presence of restrictions, physical exercise becomes difficult, and a sedentary lifestyle is inevitable. It is known that a sedentary lifestyle has a negative impact on diabetes regulation [14]. In a study conducted in Northern India, no significant change in HbA1c was found in the period when restrictions were applied compared to the pre-quarantine period [15]. In contrast to this study, there are also studies showing a significant increase in HbA1c during the restriction period [16,17]. In our study, the mean HbA1c decreased from 7.9 to 6.9 in the patient group who did not have Covid-19.

The effects of COVID-19 infection on lipid metabolism are widely discussed in the literature. In a retrospective study by Qin et al., a decrease in total cholesterol and LDL cholesterol levels was found in COVID-19 patients [18]. In a review, it was stated that the change observed in most studies on the lipid profiles of COVID-19 patients was a decrease in cholesterol and apolipoprotein levels and an increase in triglycerides [19]. However, in our study, a significant increase in LDL cholesterol, total cholesterol, and HDL cholesterol levels was detected in diabetic patients with COVID-19. It is known that the development of atherosclerotic complications is highly likely in diabetic patients [20]. It is also known that dyslipidemia poses a high risk for the development of atherosclerosis and cardiovascular diseases [21]. It should be considered that the negative effect of COVID-19 infection on the lipid profile in the medium and long term will be a problem in terms of cardiovascular diseases and mortality.

Diabetes management during the pandemic period was ensured by patients continuing their regular check-ups and complying with diet and exercise recommendations. In this period, the decrease in patients' HbA1c levels can be evaluated as a result of regular follow-up and appropriate treatment management. However, further prospective studies are needed to assess the long-term effects of COVID-19 infection in diabetic patients. Yet, it is clear that the effect on lipid profile should be evaluated with larger and prospective studies.

Our study has some limitations. The average age of patients who had Covid-19 was higher than that of patients who did not have Covid-19. Healthier results could be obtained in a population with more balanced average ages. Additionally, the lack of objective data on patients' exercise habits created limitations in interpreting the results. Other limitations of our study are that it is a retrospective study and only 6-month data were evaluated. Longer-term and prospective studies will more clearly reveal the long-term effects of Covid-19 on diabetes.

5. Conclusions

The Covid-19 pandemic poses a significant health threat to patients with diabetes. Infection prophylaxis, healthy lifestyle, and regular medical follow-up are critical in protecting diabetic patients from COVID-19 and its possible complications. In our study, it was determined that COVID-19 infection did not seriously disrupt metabolic processes in diabetic patients but caused an increase in cholesterol levels. Patients with diabetes should be followed closely in the post-infection period and complications should be minimized with appropriate treatment management.