J. Endocrinol. Invest. 14: 357-360, 1991
Elevated endogenous digitalis-like substance in hypertensive diabetic patients with afamily history of hypertension S. Okamoto, M. Ikeda, T. Morise, I. Miyamori, and R. Takeda Second Department of Internal Medicine, School of Medicine, Kanazawa University, Takaramachi 13-1, Kanazawa, Ishikawa, Japan. ABSTRACT. Endogenous digital-like substance (DLS) is increased in patients with essential hypertension and is hypothesized to playa role in the pathogeneSis of high blood pressure. Whether an increase in DLS in diabetic patients with hypertension is associated with a family history of hypertension or diabetic nephropathy was investigated. Plasma DLS was measured as Na+-K+-ATPase inhibitory activity (ATPI) in 100 Type 2 diabetic patients. Ouabain was used as a standard of Na-KATPase inhibition. Diabetic patients with hyperten-
sion demostrated a greater ATPI level than normotensive diabetic patients (p < 0.05). In patients with hypertension groups, the positive family history gruop had a higher ATPllevel than the negative family history group (p < 0.01). Microalbuminuria was not correlated with the ATPI level in diabetic patients. These results suggest that ATPI might play a role in the pathogenesis of hereditary hypertension associated with diabetes mellitus, but not have etiologic significance in diabetic nephropathy.
INTRODUCTION
steroid or steroid-sugar complex, probably originating from the adrenal gland (17). The biochemical properties of DLS and what parameters are studied in the DLS assay, remain somewhat controversial. The cross-reaction of extracted samples with digoxin-antibody, the Na+-K+-ATPase inhibitory activity in the samples, or displacement of ouabain-binding activity have all been described as potential methods of investigating DLS. In this study Na+-K+-ATPase inhibitory activity (ATPI) was measured in the plasma of diabetic patients. Data was analyzed in conjunction with information on family history in an attempt to address the genetic aspects of DLS. The relationship between ATPI and microalbuminuria as an indicator of early diabetic nephropathy was also studied.
Endogenous digitalis-like substance (DLS) is thought to be increased in patients with essential hypertension (1-5), and might pay a role in the etiology of high blood pressure in those patients, although this assertion is still controversial (6, 7). The possible relationship between DLS and hypertension bears investigation as there have been several reports on sodium transport alteration in erythrocytes and leukocytes in patients with essential hypertension along with a family history of hypertension (8-13). These same findings have been described in patients with diabetic nephropathy, a condition which may lead to hypertension (14,15) . Determining whether increased DLS in patients with hypertension with or without diabetes mellitus is associated with a family history of hypertension and diabetic nephropathy would be the next step . However, the chemical nature of DLS and even the tissue from which this putative substances is released into the circulation have not yet been clearly elucidated. Some investigators have suggested that the substance is a hypothalamic peptide (16) while it has also been suggested that it might be a
MATERIALS AND METHODS One hundred patients with Type 2 diabetes mellitus consisting of 57 males and 43 females (mean age ± SE of 63.7 ± 1.2 years) were studied. Patients with overt renal dysfunction (blood urea nitrogen levels over 40 mg/dl or serum creatinine over 2.0 mg/dl) were excluded. No patients in the study had previously received steroids or digitalis. The patients were divided into four groups according to the presence of hypertension and a family history including second degree relatives of hypertension: Group 1: Thirty-two normotensive diabetic patients without a family history of hypertension; Group 2: Fifteen nor-
Key-words: Digitalis-like substance, Na+-K+-ATPase, Na+-K+-ATPase inhibitor, diabetes mellitus, hypertension. family history. Correspondence: Shinya Okamoto, Second Departmen t of Internal Medicine. School of Medicine. Kanazawa University, Takaramachi 13-1, Kanazawa, Ishikawa, Japan. Received January 8, 1990; Accepted January 3. 1991.
357
S. Okamoto, M. Ikeda, T. Morise, et a/.
Table - Plasma A TPI and OLi in hypertensive goups (mean ± SE). Group
N
Age yr
BPs mmHg
BPd mmHg
BUN mg/dl
Cr mg/dl
ATPI pmol/ml
NT (Groups 1 and 2)
47
60.7±2.0
124.1±1,8
74,O±1.4
15.8±1,1
°
93±O.05
237±30
HT (Groups 3 and 4)
53
66,6± 1.4**
149,2±2.6**
87,2±2,3**
24,9±2.4**
1.31±O,17**
370±49*
Control
43
60,8±1.4
121.9±1.6
73.5±1.3
16.4±1,2
O,95±O.O5
~26±18
*p
Elevated endogenous digitalis-like substance in hypertensive diabetic patients with afamily history of hypertension S. Okamoto, M. Ikeda, T. Morise, I. Miyamori, and R. Takeda Second Department of Internal Medicine, School of Medicine, Kanazawa University, Takaramachi 13-1, Kanazawa, Ishikawa, Japan. ABSTRACT. Endogenous digital-like substance (DLS) is increased in patients with essential hypertension and is hypothesized to playa role in the pathogeneSis of high blood pressure. Whether an increase in DLS in diabetic patients with hypertension is associated with a family history of hypertension or diabetic nephropathy was investigated. Plasma DLS was measured as Na+-K+-ATPase inhibitory activity (ATPI) in 100 Type 2 diabetic patients. Ouabain was used as a standard of Na-KATPase inhibition. Diabetic patients with hyperten-
sion demostrated a greater ATPI level than normotensive diabetic patients (p < 0.05). In patients with hypertension groups, the positive family history gruop had a higher ATPllevel than the negative family history group (p < 0.01). Microalbuminuria was not correlated with the ATPI level in diabetic patients. These results suggest that ATPI might play a role in the pathogenesis of hereditary hypertension associated with diabetes mellitus, but not have etiologic significance in diabetic nephropathy.
INTRODUCTION
steroid or steroid-sugar complex, probably originating from the adrenal gland (17). The biochemical properties of DLS and what parameters are studied in the DLS assay, remain somewhat controversial. The cross-reaction of extracted samples with digoxin-antibody, the Na+-K+-ATPase inhibitory activity in the samples, or displacement of ouabain-binding activity have all been described as potential methods of investigating DLS. In this study Na+-K+-ATPase inhibitory activity (ATPI) was measured in the plasma of diabetic patients. Data was analyzed in conjunction with information on family history in an attempt to address the genetic aspects of DLS. The relationship between ATPI and microalbuminuria as an indicator of early diabetic nephropathy was also studied.
Endogenous digitalis-like substance (DLS) is thought to be increased in patients with essential hypertension (1-5), and might pay a role in the etiology of high blood pressure in those patients, although this assertion is still controversial (6, 7). The possible relationship between DLS and hypertension bears investigation as there have been several reports on sodium transport alteration in erythrocytes and leukocytes in patients with essential hypertension along with a family history of hypertension (8-13). These same findings have been described in patients with diabetic nephropathy, a condition which may lead to hypertension (14,15) . Determining whether increased DLS in patients with hypertension with or without diabetes mellitus is associated with a family history of hypertension and diabetic nephropathy would be the next step . However, the chemical nature of DLS and even the tissue from which this putative substances is released into the circulation have not yet been clearly elucidated. Some investigators have suggested that the substance is a hypothalamic peptide (16) while it has also been suggested that it might be a
MATERIALS AND METHODS One hundred patients with Type 2 diabetes mellitus consisting of 57 males and 43 females (mean age ± SE of 63.7 ± 1.2 years) were studied. Patients with overt renal dysfunction (blood urea nitrogen levels over 40 mg/dl or serum creatinine over 2.0 mg/dl) were excluded. No patients in the study had previously received steroids or digitalis. The patients were divided into four groups according to the presence of hypertension and a family history including second degree relatives of hypertension: Group 1: Thirty-two normotensive diabetic patients without a family history of hypertension; Group 2: Fifteen nor-
Key-words: Digitalis-like substance, Na+-K+-ATPase, Na+-K+-ATPase inhibitor, diabetes mellitus, hypertension. family history. Correspondence: Shinya Okamoto, Second Departmen t of Internal Medicine. School of Medicine. Kanazawa University, Takaramachi 13-1, Kanazawa, Ishikawa, Japan. Received January 8, 1990; Accepted January 3. 1991.
357
S. Okamoto, M. Ikeda, T. Morise, et a/.
Table - Plasma A TPI and OLi in hypertensive goups (mean ± SE). Group
N
Age yr
BPs mmHg
BPd mmHg
BUN mg/dl
Cr mg/dl
ATPI pmol/ml
NT (Groups 1 and 2)
47
60.7±2.0
124.1±1,8
74,O±1.4
15.8±1,1
°
93±O.05
237±30
HT (Groups 3 and 4)
53
66,6± 1.4**
149,2±2.6**
87,2±2,3**
24,9±2.4**
1.31±O,17**
370±49*
Control
43
60,8±1.4
121.9±1.6
73.5±1.3
16.4±1,2
O,95±O.O5
~26±18
*p
