COVID-19 and Pharmacological Treatment of Type 2 Diabetes

Bolesnici sa šećernom bolešću tipa 2 (ŠB2) su pod povećanim rizikom virusnih infekcija i pridruženih respiratornih komplikacija kao što je pneumonija. COVID-19 (Coronavirus Disease-2019) je virusna infekcija uzrokovana koronavirusom SARS-CoV-2 koja je dovela do pandemije zahvaćajući preko 100 zemalja u svijetu. Dosadašnji rezultati pokazuju da bolesnici sa ŠB2 imaju značajno veću smrtnost od COVID-19 infekcije. Upravo zbog toga važno je naglasiti moguće patofiziološke učinke farmakološkog liječenja ŠB2 na COVID-19 radi odabira optimalnog lijeka. Angiotenzinkonvertirajući enzim 2 (ACE2) te enzim dipeptidil-peptidaza 4 (DPP-4) su receptori za koronavirus, a ujedno su uključeni i u regulaciju upalnih procesa, bubrežnu i kardiovaskularnu fiziologiju te hemostazu glukoze. Metformin, zlatni standard u liječenju ŠB2, treba izbjegavati kod teže kliničke slike zbog rizika od dehidracije i laktične acidoze. Slično vrijedi i za inhibitore kotransportera natrij glukoza 2 receptora (SGLT-2 inhibitori) zbog rizika od dehidracije i euglikemijske ketoacidoze, a oni također povećavaju aktivnost bubrežnog ACE2. Preparati sulfonilureje su relativno sigurni kod oboljelih od COVID-19 infekcije uz veći rizik od hipoglikemije. DPP-4 inhibitori zbog svog imunomodulatornog učinka teoretski mogu prevenirati i reducirati rizik i progresiju akutnih respiratornih komplikacija (citokinska oluja) kod oboljelih od ŠB2. Agonisti glukagonu sličnog peptida-1 (GLP-1 agonisti) trebaju se upotrebljavati uz oprez i adekvatni unos tekućine i hrane zbog rizika od dehidracije, a također povećavaju aktivnost ACE2 u animalnim modelima. Inzulin, iako u animalnim modelima povećava bubrežnu ekspresiju ACE2, lijek je izbora kod hospitaliziranih bolesnika uz oprez zbog većeg rizika od hipoglikemije. Stručna društva preporučuju nastavak terapije inhibitorima sustava renin-angiotenzin-aldosteron (RAAS inhibitori).Patients with type 2 diabetes (DM2) are at increased risk of viral infections and related respiratory complications. COVID-19 (Coronavirus Disease-2019) is a viral infection caused by coronavirus 2 (SARS-CoV-2), that has led to a pandemic affecting more than 100 countries across the globe. Studies to date have reported that patients with DM2 are at a significantly higher mortality risk from COVID-19. Accordingly, it is important to understand shared pathophysiology pathways between effects of pharmacological drugs and COVID-19 infection in order to choose the optimal treatment of DM2. Angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase-4 (DPP-4) are coronavirus receptors that are also involved in glucose control, renal and cardiovascular physiology, and metabolic pathways including inflammation processes. Metformin, the gold standard treatment for DM2, should be avoided in patients with severe COVID-19 because of risk of dehydration and lactic acidosis. Sodiumglucose co-transporter-2 (SGLT2) inhibitors should also be avoided in patients with severe COVID-19 because of risk of dehydration and euglycemic diabetic ketoacidosis, and because they also promote renal ACE2 activity. Sulfonylureas are safe in patients with COVID-19, although there is a higher risk of hypoglycemia. Due to their immunomodulatory effect, DPP-4 inhibitors may prevent and reduce the risk and progression of acute respiratory complications (cytokine storm) in patients with DM2. Glucagon-like peptide-1 receptor (GLP-1) agonists should be used with caution, along with adequate intake of food and liquids because of higher risk of dehydration, and also because GLP-1 agonists upregulate ACE2 in animal models. Although insulin increases intrarenal ACE2 expression in animal models, insulin therapy should be prescribed in all hospitalized patients with severe or critical disease. However, regular monitoring of blood-glucose is needed. DM2 should continue with their antihypertensive regimens including renin–angiotensin–aldosterone system (RAAS) inhibitors

Inzulinska rezistencija u tipu 1 šećerne bolesti: povezanost s metaboličkim i upalnim parametrima

Although insulin resistance is usually associated with the development of type 2 diabetes, it can also be a feature of patients with type 1 diabetes. Insulin resistance has been documented in type 1 diabetes and may contribute to the high risk of cardiovascular disease in this population. To investigate the relationship of insulin resistance with metabolic and inflammatory parameters we divided 304 patients according to median estimated glucose disposal rate (eGDR =9.72 mgkg-1min-1) into lower (n=153) and higher (n=151) insulin sensitivity groups. Patients with lower insulin sensitivity had higher levels of serum lipids (except for HDL cholesterol), duration of diabetes, daily insulin dose, white blood cell count, C-reactive protein, homocysteine and ferritin. Spearman correlation analysis showed significant associations between individual components of insulin resistance and various metabolic and inflammatory parameters. Multiple logistic regression models found significant association of age, sex, duration of diabetes, serum lipids, daily insulin dose, white blood cell count and ferritin with progression to insulin resistance. The presence of insulin resistance indicates a greater risk of micro- and macrovascular disease and health care professionals need to be alerted that this subset of individuals with type 1 diabetes will require stringent control of hypertension, glycemia and serum lipids.Inzulinska rezistencija u tipu 1 šećerne bolesti dokazano doprinosi povećanom riziku razvoja kardiovaskularne bolesti. U ovoj studiji istraživana je razina inzulinske osjetljivosti koristeći kliničke parametre (eGDR ) u bolesnika sa šećernom bolešću tipa 1 i istraživan je odnos razine inzulinske osjetljivosti s metaboličkim i upalnim parametrima. Od 304 bolesnika uključena u studiju njih 153 imalo je nižu inzulinsku osjetljivost (eGDR <9.72 mgkg-1min-1), a 151 bolesnik imao je višu inzulinsku osjetljivost (eGDR ≥9.72 mgkg-1min-1). Bolesnici s nižom razinom inzulinske osjetljivosti imali su značajno više vrijednosti lipida u serumu (osim HDL kolesterola), indeks tjelesne težine, trajanje šećerne bolesti te upalne parametre, a svi navedeni čimbenici zajedno i pojedinačno doprinose razvoju mikro- i makrovaskularnih komplikacija u osoba oboljelih od šećerne bolesti tipa 1. Multiplom logističkom regresijom dokazano je da na razvoj inzulinske rezistencije u šećernoj bolesti tipa 1 utječu spol, godine života, trajanje šećerne bolesti, serumski lipidi, glikemija natašte, dnevna doza apliciranog inzulina i leukociti. Inzulinska rezistencija u tipu 1 šećerne bolesti doprinosi povećanom riziku razvoja mikro- i makrovaskularnih komplikacija, a ti pojedinci unutar skupine bolesnika sa šećernom bolešću tipa 1 zahtijevaju strožu kontrolu povišenog krvnog tlaka, glikemije i serumskih lipida

Inzulinska rezistencija u tipu 1 šećerne bolesti: povezanost s metaboličkim i upalnim parametrima

Although insulin resistance is usually associated with the development of type 2 diabetes, it can also be a feature of patients with type 1 diabetes. Insulin resistance has been documented in type 1 diabetes and may contribute to the high risk of cardiovascular disease in this population. To investigate the relationship of insulin resistance with metabolic and inflammatory parameters we divided 304 patients according to median estimated glucose disposal rate (eGDR =9.72 mgkg-1min-1) into lower (n=153) and higher (n=151) insulin sensitivity groups. Patients with lower insulin sensitivity had higher levels of serum lipids (except for HDL cholesterol), duration of diabetes, daily insulin dose, white blood cell count, C-reactive protein, homocysteine and ferritin. Spearman correlation analysis showed significant associations between individual components of insulin resistance and various metabolic and inflammatory parameters. Multiple logistic regression models found significant association of age, sex, duration of diabetes, serum lipids, daily insulin dose, white blood cell count and ferritin with progression to insulin resistance. The presence of insulin resistance indicates a greater risk of micro- and macrovascular disease and health care professionals need to be alerted that this subset of individuals with type 1 diabetes will require stringent control of hypertension, glycemia and serum lipids.Inzulinska rezistencija u tipu 1 šećerne bolesti dokazano doprinosi povećanom riziku razvoja kardiovaskularne bolesti. U ovoj studiji istraživana je razina inzulinske osjetljivosti koristeći kliničke parametre (eGDR ) u bolesnika sa šećernom bolešću tipa 1 i istraživan je odnos razine inzulinske osjetljivosti s metaboličkim i upalnim parametrima. Od 304 bolesnika uključena u studiju njih 153 imalo je nižu inzulinsku osjetljivost (eGDR <9.72 mgkg-1min-1), a 151 bolesnik imao je višu inzulinsku osjetljivost (eGDR ≥9.72 mgkg-1min-1). Bolesnici s nižom razinom inzulinske osjetljivosti imali su značajno više vrijednosti lipida u serumu (osim HDL kolesterola), indeks tjelesne težine, trajanje šećerne bolesti te upalne parametre, a svi navedeni čimbenici zajedno i pojedinačno doprinose razvoju mikro- i makrovaskularnih komplikacija u osoba oboljelih od šećerne bolesti tipa 1. Multiplom logističkom regresijom dokazano je da na razvoj inzulinske rezistencije u šećernoj bolesti tipa 1 utječu spol, godine života, trajanje šećerne bolesti, serumski lipidi, glikemija natašte, dnevna doza apliciranog inzulina i leukociti. Inzulinska rezistencija u tipu 1 šećerne bolesti doprinosi povećanom riziku razvoja mikro- i makrovaskularnih komplikacija, a ti pojedinci unutar skupine bolesnika sa šećernom bolešću tipa 1 zahtijevaju strožu kontrolu povišenog krvnog tlaka, glikemije i serumskih lipida

Waist-to-height ratio is independently associated with chronic kidney disease in overweight type 2 diabetic patients

OBJECTIVE: Chronic kidney disease (CKD) is one of the most serious complications in obesity-induced type 2 diabetes mellitus (T2DM). Body mass index (BMI), waist-to-hip ratio (WHR), waist circumference (WC) and waist-to-height ratio (WHtR) are recognised as sensitive obesity measures. We aimed to investigate the association of BMI, WC, WHR and WHtR with CKD prevalence in overweight T2DM patients. ----- DESIGN, SUBJECTS AND METHODS: We obtained 125 overweight T2DM patients coming for their in-patient annual visit. Metabolic profiles and anthropometric indices were measured and calculated. Urine albumin excretion (UAE) was determined as the mean of 24-h urine from two consecutive days. Serum creatinine was measured from fasting blood sample in order to calculate the estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration formula. Patients were divided into two groups according to CKD prevalence. ----- RESULTS: Thirty-six (28.8%) patients met diagnostic criteria for CKD. The WHtR and WC were higher in the group with CKD. WHtR correlated positively with UAE (r = 0.828, p < 0.001) and negatively with eGFR (r = -0.262, p = 0.015). No significant correlation was observed with WC in relation to UAE (p = 0.335) nor eGFR (p = 0.121). WHtR yielded the significant and great OR in association with nephropathy after adjustment for all confounding risk factors. ----- CONCLUSION: WHtR might be of a greater importance in association to CKD compared to other anthropometric parameters that indicate central obesity. Whether it is a best measure of central obesity and its exact role in CKD pathology is yet to be investigated

The role of endothelial dysfunction driven by adipocitokines in the development and progression of microvascular complications in patients with type 1 and type 2 diabetes

Micro and macrovascular complications are the leading cause of morbidity and mortality in diabetic patients. During the last decades attention has been focused on their early diagnosis and prevention. Diabetes related metabolic abnormalities: insulin resistance, hyperglycaemia and dyslipidaemia along with oxidative stress and low-grade inflammation contribute to the development of endothelial dysfunction and macrovascular complications. Recent investigations indicate a potential role of adipocitokines originating from visceral adipose tissue: adiponectin, leptin, resistin and dipepetidyl peptidase-4 (DPP-4) activity in the development of microvascular complications in diabetes. The association of these adipocitokines with the activity of endothelial synthetase (eNOS) involved into the metabolism of nitric oxide (NO) was documented in animal and cell culture studies. We hypothesize that lower adiponectin and higher leptin and resistin plasma concentration and DPP-4 activity are associated with the development and progression of diabetic microvascular complications by endothelial function impairment. A possible identification of new markers of the complex pathophysiology development and progression of microvascular complications in diabetes will contribute to improved diagnosis followed by an individualized patients approach

Upotreba antropometrijskih obilježja debljine u procjeni mikrovaskularnih komplikacija u pretilih bolesnika s tipom 2 šećerne bolesti

Waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) are superior to body mass index (BMI) in predicting type 2 diabetes mellitus (T2DM) development. The aim of this study was to investigate the predictive power of BMI, WC, WHR and WHtR for microvascular (chronic kidney disease (CKD), retinopathy and peripheral neuropathy) prevalence in obese (BMI ≥35 kg/m2) T2DM patients. This cross-sectional study included 125 T2DM patients of both genders. The validity of each test was assessed by Receiver Operating Characteristic (ROC) curves; the area under the curve (AUC) was calculated for each anthropometric parameter and microvascular complication. AUCs for WHtR were significantly higher than AUCs for WC with respect to CKD. Optimal cut-off for WHtR was >0.593 and WC >112 cm regarding CKD. The AUC for peripheral neuropathy was significant only for WHR and optimal cut-off for WHR was >1.409 with low sensitivity and high specificity. Our study demonstrated that WHtR, WC and WHR might be used as simple and noninvasive methods for detection of CKD and peripheral neuropathy in obese T2DM population.Opseg struka (OS), omjer opsega struka i bokova (OSB) i omjer opsega struka i visine (OSV) su bolji predskazatelji razvoja šećerne bolesti tipa 2 (ŠB2) nego široko upotrebljavani indeks tjelesne mase (ITM). Svrha ovoga istraživanja je bila istražiti učinkovitost ITM, OS, OSB i OSV u procjeni učestalosti mikrovaskularnih komplikacija (kronična bubrežna bolest (KBB), retinopatija i periferna neuropatija) u pretilih (ITM ≥35 kg/m2) bolesnika sa ŠB2. Ova presječna studija je uključila 125 bolesnika oba spola sa ŠB2. Dijagnostička vrijednost testova je procijenjena krivuljama ROC (engl. Receiver Operator Characteristic); područje ispod krivulje (AUC) je izračunato za svaki antropometrijski parametar i rizični čimbenik (mikrovaskularnu komplikaciju). AUC za OSV je bio značajno viši nego AUC za OS za KBB. Optimalna granična vrijednost za OSV je bila >0,593, a za OS >112 cm za KBB. AUC za perifernu neuropatiju je bio značajan samo za OSB i optimalna granična vrijednost za OSB je bila >1,409, uz nisku osjetljivost i visoku specifičnost. Rezultati našega istraživanja ukazuju na to da OSV, OS i OSB mogu biti jednostavna i neinvazivna metoda procjene učestalosti KBB i periferne neuropatije u pretilih bolesnika sa ŠB2

Circulating dipeptidyl peptidase-4 activity is associated with insulin resistance in type 1 diabetic patients

AIM: The pathophysiology of insulin resistance (IR) comprises a complex adipokine mediated cross-talk between white adipose tissue and other organs. Dipeptidyl peptidase-4 (DPP4) is protease recently proposed as a novel adipokine linked to IR. We aimed to assess the relationship between fasting serum DPP4 activityand IR in type 1 diabetic (T1DM) patients. ----- METHODS: A cross-sectional study comprised 44 T1DM patients aged >18 and <65years. IR was esimated using the equation for insulin sensitivity derived from euglycemic-hyperinsulinemic clamp studies-estimated glucose disposal rate (eGDR). DPP4 serum activity was determined spectrophotometrically as a rate of cleavage of 7-Amino-4-Methyl Coumarin (AMC) from H-Gly-Pro-AMC. ----- RESULTS: Patients were divided according to DPP4 activity tertiles (<25.40; ≥36.54 U/L). Fasting serum DPP4 activity was related to disease duration (p=0.012), systolic (p=0.009) and diastolic (p=0.047) blood pressure, waist circumference (p=0.037), urine albumin excretion (p=0.022) and conversely related to eGDR (p=0.004). The linear regression has shown that eGDR decreases for 0.203 mgkg(-1)min(-1) by each increase of serum DPP4 activity of 1 U/L (p<0.001) after adjustment for adjusted for age, gender, disease duration, albuminuria and the use of antihypertensives and statins. ----- CONCLUSION: Serum DPP4 activity is associated with IR in T1DM patients and it might play an important role in its pathophysiology

Circulating dipeptidyl peptidase-4 activity is associated with diabetic retinopathy in type 1 diabetic patients

PURPOSE: Diabetic retinopathy (DR) is the most frequent complication among patients with type 1 diabetes mellitus (T1DM). Dipeptidyl peptidase-4 (DPP4) is a protease with elevated activity in patients with T1DM. Several studies indicate that DPP4 inhibitors might have beneficial effect on nonproliferative retinopathy (NPR) development as well as on its progression to proliferative retinopathy (PR). We aimed to explore the relationship between serum DPP4 activity and DR in patients with T1DM. ----- METHODS: This cross-sectional study recruited 44 patients with T1DM. The DPP4 activity was measured by colorimetric assay in a microplate reader. Photodocumented retinopathy status was made according to the EURODIAB protocol. ----- RESULTS: A total of 28 (63.6%) patients were men, mean age 45.36 years, diabetes duration 23.71 years, glycated hemoglobin A1c (HbA1c) 7.4%. Patients were stratified into 2 groups according to retinopathy prevalence. Group 1 comprised 14 (31.85%) patients with DR absence while the second group consisted of 30 (68.15%) patients with both PR and NPR. Group 1 had lower fasting serum DPP4 activity (25.85 vs 33.84 U/L, p&lt;0.001) when compared to the second group. In the binary logistic regression model adjusted for age, sex, diabetes duration, and HbA1c level, DPP4 activity was associated with DR prevalence (odds ratio 1.887 [1.073-3.321]). ----- CONCLUSIONS: Serum DPP4 activity may be independently associated with both DR types in patients with T1DM. Further study is warranted to elucidate whether there is an association between DPP4 activity and DR severity and/or progression

Heart rate and blood pressure is associated with renal function in patients with type 1 diabetes in the absence of nephropathy and therapeutical interventions

Background. Albuminuria, heart rate (HR) and blood pressure are established predictors of chronic kidney diseaseand cardiovascular disease. The objective of this study was to explore the relationship between HR, systolic bloodpressure (SBP) and diastolic blood pressure (DBP) with renal function parameters in patients with type 1 diabetes(T1DM) without therapeutical interventions. Material and methods. Study included 313 normoalbuminuric T1DM. HR was determined using a standard12-lead ECG and blood pressure with a mercury sphygmomanometer, both after a resting period of 10 minutes.Urinary albumin excretion rate (UAE) was measured from at least two 24-h urine samples. Data on serum creatininelevels, age, sex and race were used to calculate the estimated glomerular filtration rate (eGFR) using the ChronicKidney Disease Epidemiology Collaboration (CKD-EPI) formula. Results. eGFR was significantly associated with duration of diabetes, HbA1c, LDL-cholesterol, and HDL-cholesterol(for the duration of diabetes r = –0.29, p &lt; 0.001). UAE significantly correlated with duration of diabetes,HDL-cholesterol, triglycerides, HR and DBP (for HR and DBP r = 0.21–0.23, p &lt; 0.001). Subjects in the 4th quartileof UAE had significantly higher HR rate compared to subjects in 1st, 2nd, and 3rd quartiles (70 ± 11 vs. 74 ± 12vs. 74 ± 12 vs. 79 ± 13 beats/min, p = 0.001). Conclusions. Results of our study suggest that interplay between HR with renal function parameters is present evenin T1DM with normal renal function

Estimated Glucose Disposal Rate in Assessment of Renal Function in Patients with Type 1 Diabetes

Insulin resistance has been documented in type 1 diabetes and may contribute to the high risk for cardiovascular disease in this population and progression of nephropathy. We investigated associations of renal parameters, including urinary albumin excretion rate (UAE), serum creatinine and creatinine clearance, with surrogate measure of insulin sensitivity calculated using a formula derived from euglycemic-hyperinsulinemic clamp studies (estimated glucose disposal rate, eGDR). Study included 353 patients with type 1 diabetes, none showed signs of adrenal, thyroid, renal, or cardiovascular diseases. Insulin sensitivity was measured with eGDR calculated with the equation: 24.31–(12.22´WHR)– (3.29´HT)–(0.57´HbA1c). The units were mgkg–1min–1; WHR=waist to hip ratio; HT=hypertension. Correlations and logistic regression analysis were performed to identify relationships between renal parameters and eGDR, individual components of insulin resistance and risk of insulin resistance. UAE and serum creatinine significantly correlated with insulin resistance measured by eGDR (r=–0.13, and –0.17, all p<0.05), and its components disorders, WHR and HbA1c. After stratifying patients in quartiles of eGDR, those in the upper quartile of the eGDR had significantly reduced levels of UAE and serum creatinine, compared to subjects in lowest quartile. In a logistic regression analysis risk for development of insulin resistance in our subjects were independently predicted only by UAE (odds ratio=1.01, p<0.01). Our results provide evidence of associations between insulin resistance and its components disorders with renal parameters, such as UAE and serum creatinine. Insulin resistance, measured with eGDR, predicts the increment in UAE in subjects with type 1 diabetes. Since progression to microalbuminuria is likely to occur in majority of diabetic patients, there is a need to further explore the role of risk factors such as insulin resistance