Acta Diabetol DOI 10.1007/s00592-015-0747-7
LETTER TO THE EDITOR
Chronic inflammation in offspring of patients with type 2 diabetes and albuminuria Angela De Matthaeis1 • Antonia Di Lorenzo1 • Alessia Gargano1 • Gianluigi Vendemiale2 • Simonetta Bacci1 • Salvatore De Cosmo1
Received: 27 February 2015 / Accepted: 24 March 2015 Ó Springer-Verlag Italia 2015
Albuminuria, a key feature of diabetic nephropathy, is one of the strongest predictors of cardiovascular events in patients with type 2 diabetes (T2DM) [1]. Moreover, it is well known the role for chronic inflammation (CI) as underlying pathogenic mechanism of atherosclerosis in non-diabetic and diabetic subjects. Recent evidences show that CI is also as a potential mediator between albuminuria and macrovascular disease [2]. Fibrinogen and C-reactive protein (CRP), both markers of inflammatory response, are consistently associated with the future cardiovascular events also in apparently healthy individuals [3]. Several data show an increased CI response in nondiabetic first-degree relatives of patients with T2DM [4, 5]. Aim of the present study was to investigate whether albuminuria in parents with T2DM affect the inflammatory status in non-diabetic offspring. Accordingly, we studied 79 non-diabetic (ADA criteria) offspring of 57 parents with T2DM (ADA criteria). Patients (26 M/31F) had 73 ± 7 years of age and 16 ± 9 years of diabetes duration. Twenty-seven had normoalbuminuria, and 30 had increased urinary albumin excretion defined as urinary albumin–creatinine ratio C2.5 in male and C3.5 mg/mmol in female or urinary albumin concentration C20 mg/l.
Managed by Massimo Porta. & Salvatore De Cosmo [email protected] 1
Unit of Internal Medicine, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
2
Unit of Internal Medicine, University of Foggia, Foggia, Italy
All 79 offspring had measured fasting serum insulin, plasma glucose, and HbA1c and underwent an oral glucose tolerance test to exclude the presence of diabetes. HOMA was assessed by the following formula: [(fasting insulin (microU/L) 9 fasting glucose (nmol/L)/22.5)]. Urinary albumin excretion was also calculated and expressed as urinary albumin–creatinine ratio (ACR). Forty-three (26 siblings of 10 families) were offspring of 27 parents with T2DM and normoalbuminuria (Alb-), and 36 (11 siblings of 5 families) were offspring of 30 parents with T2DM and increased urinary albumin excretion (Alb?) (Table 1). The generalized estimating equation procedure was performed to test the differences between the two groups after adjustment for covariates, taking into account the presence of siblings. A p value \ 0.05 was considered to indicate statistical significance. While no differences we detected between Alb? and Alb- in clinical and metabolic features as reported in the table, levels of fibrinogen (by Clauss assay) and high sensitivity C-reactive protein (hsCRP) (by immunonephelometry) were significantly higher in Alb? as compared to Alb- (291 ± 7 versus 269 ± 8 mg/dl, p = 0.043 and 0.54 ± 0.07 versus 0.37 ± 0.02 mg/dl, p = 0.033), after adjustment for age, sex, BMI and smoke. Interestingly, the further adjustment for blood pressure values, LDL cholesterol, triglycerides, HOMA ir and ACR levels and even for the occurrence of familial cardiovascular events (defined as myocardial infarction or stroke occurred in parents before 60 years of age) did not affect the difference in levels of fibrinogen and hsCRP between the two groups (p = 0.006 and p = 0.036, Alb? vs. Alb-, respectively). In conclusion, our data show as offspring of parents with T2DM, and albuminuria has higher levels of fibrinogen and hsCRP than offspring of parents with T2DM and
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Acta Diabetol Table 1 Clinical features of 43 offspring of type 2 diabetic patients without albuminuria (Alb-) and 36 offspring of type 2 diabetic patients with albuminuria (Alb?)
Alb-
Alb?
Unadjusted p value
Gender M/F
13/30
15/21
n.s.
Age (years)
44 ± 5
43 ± 6
n.s. n.s.
BMI (kg/m2)
27 ± 4
29 ± 6
Smokers
29/14
29/7
n.s.
FPG (mg/dl)
88.5 ± 15.0
88.7 ± 9.5
n.s.
2 h OGTT plasma glucose (mg/dl)
100.8 ± 31.9
106.6 ± 29.3
n.s.
HbA1c (%)
5.7 ± 0.6
5.6 ± 0.3
n.s.
Serum insulin (lU/ml)
8.7 ± 4.3
10.9 ± 7.3
n.s.
HOMA ir
1.9 ± 1.0
2.4 ± 1.8
n.s.
SBP (mmHg)
118 ± 14
116 ± 12
n.s.
DBP (mmHg)
73 ± 9
71 ± 7
n.s.
Plasma triglycerides (mg/dl)
97 ± 57
101 ± 50
n.s.
HDL cholesterol (mg/dl)
55 ± 15
58 ± 18
n.s.
LDL cholesterol (mg/dl)
128 ± 38
132 ± 36
n.s.
ACR (mg/mmol) Fibrinogen (mg/dl)
1.3 ± 1.8 269 ± 8
2.7 ± 4.4 291 ± 7^
n.s. 0.04
hsCRP (mg/dl)
0.37 ± 0.02
0.54 ± 0.07^^
0.02
BMI body mass index, FPG fasting plasma glucose, HbA1c glycated hemoglobin, HOMA ir homeostatic model assessment of insulin resistance, SBP systolic blood pressure, DBP diastolic blood pressure, HDL cholesterol high-density lipoprotein cholesterol, LDL cholesterol low-density lipoprotein cholesterol, ACR urinary albumin/creatinine ratio, hsCRP high-sensitivity C-reactive protein ^
p = 0.04;
^^
p = 0.02
normoalbuminuria. The present data suggest that albuminuria in T2DM parents affects CI status in non-diabetic offspring. These subjects may be, therefore, exposed to an increased risk of early atherosclerosis; thus, they should be monitored for preventing possible early cardiovascular events. Conflict of interest Angela De Matthaeis, Antonia Di Lorenzo, Alessia Gargano, Gianluigi Vendemiale, Simonetta Bacci, and Salvatore De Cosmo, declare no conflict of interest. Ethical standard All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent Informed consent was obtained from all patients for being included in the study.
123
References 1. Mattock MB, Morrish NJ, Viberti GC et al (1992) Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 41:735–741 2. Festa A, D’Agostino R Jr, Howard G et al (2000) Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the Insulin Resistance Atherosclerosis Study. Kidney Intern. 58:1703–1710 3. Collaboration Emerging Risk Factors, Kaptoge S, Di Angelantonio E, Pennells L et al (2012) C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 367:1310–1320 4. Ruotsalainen E, Salmenniemi U, Vauhkonen I et al (2006) Changes in inflammatory citokines are related to impaired glucose tolerance in offspring of type 2 diabetic subjects. Diabetes Care 29:2714–2720 5. Tesauro M, Rizza S, Iantorno M et al (2007) Vascular, metabolic and inflammatory abnormalities in normoglycemic offspring of patients with type 2 diabetes mellitus. Metabolism 56:413–419
LETTER TO THE EDITOR
Chronic inflammation in offspring of patients with type 2 diabetes and albuminuria Angela De Matthaeis1 • Antonia Di Lorenzo1 • Alessia Gargano1 • Gianluigi Vendemiale2 • Simonetta Bacci1 • Salvatore De Cosmo1
Received: 27 February 2015 / Accepted: 24 March 2015 Ó Springer-Verlag Italia 2015
Albuminuria, a key feature of diabetic nephropathy, is one of the strongest predictors of cardiovascular events in patients with type 2 diabetes (T2DM) [1]. Moreover, it is well known the role for chronic inflammation (CI) as underlying pathogenic mechanism of atherosclerosis in non-diabetic and diabetic subjects. Recent evidences show that CI is also as a potential mediator between albuminuria and macrovascular disease [2]. Fibrinogen and C-reactive protein (CRP), both markers of inflammatory response, are consistently associated with the future cardiovascular events also in apparently healthy individuals [3]. Several data show an increased CI response in nondiabetic first-degree relatives of patients with T2DM [4, 5]. Aim of the present study was to investigate whether albuminuria in parents with T2DM affect the inflammatory status in non-diabetic offspring. Accordingly, we studied 79 non-diabetic (ADA criteria) offspring of 57 parents with T2DM (ADA criteria). Patients (26 M/31F) had 73 ± 7 years of age and 16 ± 9 years of diabetes duration. Twenty-seven had normoalbuminuria, and 30 had increased urinary albumin excretion defined as urinary albumin–creatinine ratio C2.5 in male and C3.5 mg/mmol in female or urinary albumin concentration C20 mg/l.
Managed by Massimo Porta. & Salvatore De Cosmo [email protected] 1
Unit of Internal Medicine, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
2
Unit of Internal Medicine, University of Foggia, Foggia, Italy
All 79 offspring had measured fasting serum insulin, plasma glucose, and HbA1c and underwent an oral glucose tolerance test to exclude the presence of diabetes. HOMA was assessed by the following formula: [(fasting insulin (microU/L) 9 fasting glucose (nmol/L)/22.5)]. Urinary albumin excretion was also calculated and expressed as urinary albumin–creatinine ratio (ACR). Forty-three (26 siblings of 10 families) were offspring of 27 parents with T2DM and normoalbuminuria (Alb-), and 36 (11 siblings of 5 families) were offspring of 30 parents with T2DM and increased urinary albumin excretion (Alb?) (Table 1). The generalized estimating equation procedure was performed to test the differences between the two groups after adjustment for covariates, taking into account the presence of siblings. A p value \ 0.05 was considered to indicate statistical significance. While no differences we detected between Alb? and Alb- in clinical and metabolic features as reported in the table, levels of fibrinogen (by Clauss assay) and high sensitivity C-reactive protein (hsCRP) (by immunonephelometry) were significantly higher in Alb? as compared to Alb- (291 ± 7 versus 269 ± 8 mg/dl, p = 0.043 and 0.54 ± 0.07 versus 0.37 ± 0.02 mg/dl, p = 0.033), after adjustment for age, sex, BMI and smoke. Interestingly, the further adjustment for blood pressure values, LDL cholesterol, triglycerides, HOMA ir and ACR levels and even for the occurrence of familial cardiovascular events (defined as myocardial infarction or stroke occurred in parents before 60 years of age) did not affect the difference in levels of fibrinogen and hsCRP between the two groups (p = 0.006 and p = 0.036, Alb? vs. Alb-, respectively). In conclusion, our data show as offspring of parents with T2DM, and albuminuria has higher levels of fibrinogen and hsCRP than offspring of parents with T2DM and
123
Acta Diabetol Table 1 Clinical features of 43 offspring of type 2 diabetic patients without albuminuria (Alb-) and 36 offspring of type 2 diabetic patients with albuminuria (Alb?)
Alb-
Alb?
Unadjusted p value
Gender M/F
13/30
15/21
n.s.
Age (years)
44 ± 5
43 ± 6
n.s. n.s.
BMI (kg/m2)
27 ± 4
29 ± 6
Smokers
29/14
29/7
n.s.
FPG (mg/dl)
88.5 ± 15.0
88.7 ± 9.5
n.s.
2 h OGTT plasma glucose (mg/dl)
100.8 ± 31.9
106.6 ± 29.3
n.s.
HbA1c (%)
5.7 ± 0.6
5.6 ± 0.3
n.s.
Serum insulin (lU/ml)
8.7 ± 4.3
10.9 ± 7.3
n.s.
HOMA ir
1.9 ± 1.0
2.4 ± 1.8
n.s.
SBP (mmHg)
118 ± 14
116 ± 12
n.s.
DBP (mmHg)
73 ± 9
71 ± 7
n.s.
Plasma triglycerides (mg/dl)
97 ± 57
101 ± 50
n.s.
HDL cholesterol (mg/dl)
55 ± 15
58 ± 18
n.s.
LDL cholesterol (mg/dl)
128 ± 38
132 ± 36
n.s.
ACR (mg/mmol) Fibrinogen (mg/dl)
1.3 ± 1.8 269 ± 8
2.7 ± 4.4 291 ± 7^
n.s. 0.04
hsCRP (mg/dl)
0.37 ± 0.02
0.54 ± 0.07^^
0.02
BMI body mass index, FPG fasting plasma glucose, HbA1c glycated hemoglobin, HOMA ir homeostatic model assessment of insulin resistance, SBP systolic blood pressure, DBP diastolic blood pressure, HDL cholesterol high-density lipoprotein cholesterol, LDL cholesterol low-density lipoprotein cholesterol, ACR urinary albumin/creatinine ratio, hsCRP high-sensitivity C-reactive protein ^
p = 0.04;
^^
p = 0.02
normoalbuminuria. The present data suggest that albuminuria in T2DM parents affects CI status in non-diabetic offspring. These subjects may be, therefore, exposed to an increased risk of early atherosclerosis; thus, they should be monitored for preventing possible early cardiovascular events. Conflict of interest Angela De Matthaeis, Antonia Di Lorenzo, Alessia Gargano, Gianluigi Vendemiale, Simonetta Bacci, and Salvatore De Cosmo, declare no conflict of interest. Ethical standard All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent Informed consent was obtained from all patients for being included in the study.
123
References 1. Mattock MB, Morrish NJ, Viberti GC et al (1992) Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 41:735–741 2. Festa A, D’Agostino R Jr, Howard G et al (2000) Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the Insulin Resistance Atherosclerosis Study. Kidney Intern. 58:1703–1710 3. Collaboration Emerging Risk Factors, Kaptoge S, Di Angelantonio E, Pennells L et al (2012) C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 367:1310–1320 4. Ruotsalainen E, Salmenniemi U, Vauhkonen I et al (2006) Changes in inflammatory citokines are related to impaired glucose tolerance in offspring of type 2 diabetic subjects. Diabetes Care 29:2714–2720 5. Tesauro M, Rizza S, Iantorno M et al (2007) Vascular, metabolic and inflammatory abnormalities in normoglycemic offspring of patients with type 2 diabetes mellitus. Metabolism 56:413–419
