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Diabetes induced by neonatal streptozotocin treatment in spontaneously hypertensive and normotensive rats
Diabetes Induced by Neonatal Streptozotocin Treatment in Spontaneously Hypertensive and Normotensive Rats M. Iwase, M. Kikuchi, K. Nunoi, M. Wakisaka, Y. Maki, S. Sadoshima, and M. Fujishima The development of non-insulin-dependent diabetes melliiua (NIDDM) induced by neonatal streptozotocin (STZ) treatment was compared between male spontaneously hypertensive rata (SHR) end normotensive Wistar Kyoto rata (WKY). The animah were intreparitoneally given 37.8, 50.0, 02.5, or 76.0 mg/ kg of STZ at two days of age. At two days after STZ injection, plasma glucose was elevated in both groups of rata according to the dose of STZ, but the level was higher in SHR than in corresponding WKY. At ten days of age, plasma glucose in WKY returned to the similar level to that in vehide-treated control irrespective of the doses of STZ, while in SHR it remained above control and its level was significantly higher than that in WKY. At 12 weeks of age, plasma glucose was within the control range in WKY. while in SHR it waa markedly and dose-dependently elevated. The present study indicates that SHR are susceptible to NIDDM induced by neonatal STZ treatment. The difference in response to STZ between SHR and WKY was discussed. @ 1987 byeGrune & Stratton, Inc.
I
T IS well-known that hypertension is frequently associated with non-insulin-dependent diabetes mellitus (NIDDM) in human, and the recent epidemiologic studies
have shown that the combination of these two diseases is significant and independent of age, obesity, or antihypertensive medications.‘** However, it is difficult to disclose the mechanisms of this combination because the pathogenesis of NIDDM and hypertension as well is very complicated. Recently, Portha et al3 and Bonner-Weir et al” have developed a new rat model of NIDDM, which is experimentally induced by neonatal streptozotocin (STZ) treatment. Adopting this technique, we designed the present study to make an animal model of NIDDM with hypertension. For this purpose, male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) as controls were used. As the results indicated, we found the unexpected and remarkable difference in the development of diabetes between two groups of rats. MATERIALS AND METHODS SHR were from an inbred colony that had been maintained in our laboratory since 1973, and WKY were purchased from Charles River Laboratories (Atsuki, Japan). The animals were bred in Specific Pathogen Free condition in Kyushu University Animal Center, where temperature (24OC), humidity (60%), and lighting (on 8 AM to 8 PM) were well-controlled. They had free access to tap water and standard chow diet, which contained carbohydrate in 5 1.6%,protein in 24.8%, minerals in 7.0%. fat in 4.4%. and cellulose in 3.5% (Clea Japan Inc. Tokyo). Two-day-old male SHR and WKY neonates were intraperitoneally injected through a 27-gauge microsyringe with STZ (Upjohn Co, Kalamazoo, MI) dissolved in 0.1 mol/L citrate buffer, pH 4.5. Doses of STZ given were varied as 37.5, 50.0, 62.5, and 75.0 mg/kg, but the injection volume was the same (4 rL/g body weight). Control rats received an equivalent amount of citrate buffer alone. The neonates were left with their own mother and weaned at 4 weeks of age.
From the Second Department of Internal Medicine, Fact&y of Medicine, Kyushu University, Fukuoka, Japan. Address reprint requests to Masanori Iwase, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-l-1, Higashi-ku. Fukuoka City, 812, Japan. o I987 by Grune & Stratton, Inc. 0026-0495/87/3607-0009$03.00~0 654
Body weight was measured weekly until the age of 12 weeks. Blood samples were obtained by cardiac puncture with a 28-gauge syringe at four and ten days of age, and by snipping the tail in a fed state (6 PM) after 3 weeks of age. Plasma glucose was measured by a Beckman Glucose Analyzer 2 (Beckman Instruments Inc, Fullerton, CA). At 12 weeks of age, both SHR and WKY, which received either vehicle or 75.0 mg/kg of STZ, were put into metabolic cages for 24 hours for a metabolic study. We measured one-day food and water intake, urine volume, and urinary glucose. At that time, a blood sample was taken as above mentioned and used for determination of glycosylated hemoglobin (GHb) by aminophenylboronic acid affinity chromatography (Isolab, Akron, OH). Blood pressure was measured in unanesthetized state by an indirect tail-cuff method at 11 or 12weeksofage. For statistical analysis, a two-tailed unpaired Student’s t-test was used. The result was considered to be significant when the P value was less than .05. RESULTS The serial changes of nonfasting plasma glucose level throughout the experimental course in SHR (Fig IA) and in
WKY (Fig 1B) received vehicle or 75.0 mg/kg of STZ at two days of age are demonstrated. Plasma glucose was elevated two days after the administration of STZ in either SHR or WKY. At ten days and 3 weeks of age, however, plasma glucose level in WKY fell and returned to the level of vehicle-treated control, while in SHR it fell but was still significantly higher than that in control. Thereafter, overt hyperglycemia gradually developed in SHR, while only mild hyperglycemia did in WKY. Figure 2 shows the relationship between STZ dose and plasma glucose level in SHR and WKY at 4 days, 10 days, and 12 weeks of age. At four days of age, ie, two days after STZ injection (Fig 2A), plasma glucose was elevated according to STZ dose given in both rats. Although the glycemic level was slightly higher in SHR than that in WKY, the difference did not reach the statistical significance at larger doses of STZ. The glycemic level in WKY treated with 50.0 mg/kg of STZ was comparable to that in SHR treated with 37.5 mg/kg of STZ. At ten days of age (Fig 2B), plasma glucose returned to the control level in WKY irrespective of the doses of STZ given, while in SHR it was above the control (vehicle-treated) level and was significantly higher than that in WKY. At 12 weeks of age (Fig 2C), plasma glucose was markedly and STZ dose-dependently elevated in Met&o/&n, Vol36, No 7 (July), 1987: op 654-657
NIDDM IN SHR AND WKY
655
..1
.
.
.
5HR
itreptozobcin /
Streptozobcin(mg/kg)
*,I-..
a
n=8
._*__“______*____--~-----_*_-----~
4
8
12
Age (weeks)
Fig 2. The relationship between doee of ST2 and nonfesting plasma glucose level at verioue ages in male SHB (a) and normotanstve WKY rats Cm given ST2 at two days, of age. The numbers of animaJa are 8 SHB and 9 WKY for vehicle. 10 and 6 for 37.6 mglkg STZ. 7 and 2 for BO.0 mglkg BTZ. 9 and 4 for 82.6 mglkg STZ. and Band 4 for 76.0 mglkg ST&treated group, reegectiveiy. *PC .06,**Pc .Ol, ?? **P.: .OOl BHR vWKY.Resuttsaremean + BEM. (AL 4 days; (B), 10 dqs: ICI. 12 weeks.
or Vehicle
n=4 n=9
1
4
I
8
12
Age (weeks) Fig 1. Changes in nonfasting plasma glucose level in (A) male 8HR and (B) normotensive WKY rets treated with vehide (-----I or at two days of age. ?? P < 76.0 mg/kg of streptozotocin (-1 .06, ?? *P d .Ol. ?? **P c .OOl v control. Results are mean f SEM.
SHR, while in WKY it remained at the control level. A clear difference was seen between SHR and WKY. As shown in Table 1, body weight at age 12 weeks was significantly smaller in SHR than that in WKY of vehicletreated control (P < .Ol), as well as STZ-treated groups. Body weight was reduced with dose of STZ given, such reduction being more marked in SHR. As shown in Table 2, GHb, food and water intakes, urine volume, and urinary glucose were markedly increased in SHR treated with 75.0 mg/kg of STZ compared to vehicletreated control. By contrast, these variables did not differ between vehicle- and STZ-treated groups in WKY, in which urinary glucose was not detected. There were no differences in systolic blood pressure between STZ-treated and control animals in either SHR or WKY. DISCUSSION
In the present study, the susceptibility to the development of NIDDM induced by neonatal STZ treatment was mark-
edly increased in SHR compared to WKY. Some factors could contribute to this clear difference. First, SHR may have glucose intolerance genetically because impaired glucose tolerance has been reported in SHR from 5 weeks of age: and also B cell mass of pancreatic islets was reduced by 50% in young SHR compared to normotensive Wistar rats of the same age.6 In the present results, however, nonfasting plasma glucose was substantially the same at any age between SHR and WKY of vehicle-treated group, and their GHb levels were also similar. Thus, genetically impaired glucose tolerance is unlikely in SHR. Second, SHR may be more sensitive to STZ than WKY in neonatal periods. In fact, plasma glucose at two days after STZ injection was higher in SHR than in WKY, although plasma glucose in WKY received 50.0 mg/kg and more of STZ was elevated to the comparable level to that in SHR received 37.5 or 50.0 mg/kg of STZ. It is unlikely that the changes of plasma glucose level after this initial hyperglycemia were affected by STZ itself because STZ has no long-acting effects on pancreatic islets.7 Therefore, the marked difference in the glycemic level at 12 weeks of age in this study could not be explained only by the mild difference in the sensitivity to STZ. Third, the regeneration capacity of B cells might account for the difference. It is interesting that WKY develop overt hyperglycemia by STZ treatment in adult’ but not in neonate. In the adult STZ model, persistent hyperglycemia and B cell necrosis occur immediately after STZ treatment. In the neonatal STZ model, however, the regeneration of B cell in pancreatic islets occurs after the insult of STZ, resulting in a recovery from an initial hyperglycemia.4 In this study, plasma glucose in WKY returned to the control level at ten days of age irrespective of the doses of STZ given, but in SHR it remained above the control level, suggesting that the regeneration of B cells could be sufficient in WKY but insufficient in SHR. As a result, reduced B cell mass in
IWASE ET AL
656
Table 1.
BodyWeight
of 12-Week-Old
SHR and Normotensive WKY Rats Given Vehicle or Various Doses of
Streptozotooin at Two Days of Age Streptcuotocin(me/kg)
SHR No.
10
8
Body weight (g)
9
9
203 + 4t
194 f 5t
7 214 ? 3.
249 4 6
248 + 8
75.0
62.5
50.0
37.5
Vehicle
WKY 5
9
No. Body weight (g)
4
4
247 f 5$
261 * 9+
2
271 j, 14
287 + 6
272
Values are mean f SEM. ?? P c .05 Y vehicla-treatedSHA or WKY. t P -c .OO 1 v vehicle-treated SHR or WKY. SP -c .Ol
v vehicle-treated SHR or WKY.
Table 2. Some Characteristics of 12-Week-Old
SHR and WKY Rats Given Vehicle or 75.0 mg/kg of ST2 at Two Days of Ago SHR
WKY
Vehicle
ST2
Vehicle
8
9
9
4
4.7 + 0.1
12.9 f 0.8*
5.0 t 0.4
5.6 + 0.5
No. Glycosylatedhemoglobin (%I
ST-Z
18.1 + 1.5
18.5 + 1.6
Water intake (mL/d)
38 + 3
106 f 8.
32 f 3
32 f 3
Urine volume (mL/d)
14 f 2
77 * 7f
13 * 2
12 t 2
Urinary glucose (g/d)
0
Food intake (g/d)
Systolic blood pressure (mm Hg)
18.4 + 1.7
208
28.9
+ l.l*
7.2 + 0.7’
f 5
206
+ 4
0 155 + 5
0 153 f 5
Results are mean f SEM. ?? P i
,001 Y vehicle-treated SHR.
SHR may lead to the exhaustion of B cells with lateoccurring severe hyperglycemia in adult periods. This interesting observation needs further study to be clarified for its mechanism. An increased insulin resistance is considered to be one of the pathogenetic mechanisms in the development of NIDDM in patients with hypertension because hyperinsulinemia has been demonstrated in oral glucose tolerance test? or postprandially9 in hypertensive patients. Such an increased insulin resistance could lead to a compensatory B cell regeneration and hyperplasia, and it may be speculated that diabetes becomes manifest when the regeneration of B cells cannot meet an increased insulin demand.” The genetically determined capacity for B cell regeneration has been shown from the studies of diabetic animal models such as diabetic
mouse,” diabetic Chinese hamster,‘* and diabetes after subtotal pancreatectomy in five strains of rats.13 Our present results suggest that this capacity is reduced in SHR compared to that in WKY. SHR, which were separated from WKY in 1963,” genetically develop spontaneous hypertension, and have been used worldwide as a model of human essential hypertension. Therefore, it might be interesting to take account of the capacity for B cell regeneration as well as an increased insulin resistance in patients with hypertension. In conclusion, male SHR and WKY were treated with various doses of STZ at two days of age and maintained for 12 weeks. As a result, only SHR developed NIDDM. The reduced capacity for B cell regeneration in SHR might account for this outstanding difference.
REFERENCES 1. Barrett-Connor
E, Criqui MH, Klauber MR, et al: Diabetes and hypertension in a community of older adults. Am J Epidemiol 113:276-284, 1981 2. Modan M, Halkin H, Almog S, et al: Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. J Clin Invest 75:809-817, 1985 3. Portha B, Picon L, Rosselin G, et al: Chemical diabetes in the adult rat as the spontaneous evolution of neonatal diabetes. Diabetologia 17:371-377, 1979 4. Bonner-Weir S, Trent DF, Honey RN, et al: Responses of neonatal rat islets to streptozotocin. Limited B-cell regeneration and hyperglycemia. Diabetes 30:64-69, 198 1 5. Yamori Y, Ohtaka M, Ueshima H, et al: Glucose tolerance in spontaneously hypertensive rats. Jpn Circ J 42:841-847, 1978
6. Postnov YV, Gorkova SI, Solovyova LP, et al: Reduction of B-cell component of pancreatic islets in spontaneously hypertensive rats. Virchows Arch 371:79-87, 1976 7. Bell RH Jr, Hye RJ: Animal models of diabetes mellitus, Physiology and pathology. J Surg Res 35:433-460, 1983 8. Somani P, Singh HP, Saini RK, et al: Streptozotocin-induced diabetes in the spontaneously hypertensive rat. Metabolism 28: 10751077,1979 9. Singer P, GiMicke W, Voigt S, et al: Postprandial hyperinsulinemia in patients with mild essential hypertension. Hypertension 7:182-186, 1985 10. Hellerstram C, Andersson A, Gunnarsson R, et al: Regeneration of islet cells. Acta Endocrinol 205:145-160, 1976 (suppl) 11. Coleman DL, Hummel KP: The influence of genetic back-
NIDDM IN SHR AND WKY
ground on the expression of the obese (ob) gene in the mouse. Diabetologia 9:287-293, 1973 12. Like AA, Gerritsen GC, Duhn WE, et al: Studies in the diabetic Chinese hamster: Light microscopy and autoradiography of pancreatic islets. Diabetologia 10:501-508,1974
657
13. Kaufmann F, Rodriguez RR: Subtotal pancreatectomy in five different rat strains. Incidence and course of development of diabetes. Diabetologia 27~38-43, 1984 14. Okamoto K, Aoki K: Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282-293, 1963
I
T IS well-known that hypertension is frequently associated with non-insulin-dependent diabetes mellitus (NIDDM) in human, and the recent epidemiologic studies
have shown that the combination of these two diseases is significant and independent of age, obesity, or antihypertensive medications.‘** However, it is difficult to disclose the mechanisms of this combination because the pathogenesis of NIDDM and hypertension as well is very complicated. Recently, Portha et al3 and Bonner-Weir et al” have developed a new rat model of NIDDM, which is experimentally induced by neonatal streptozotocin (STZ) treatment. Adopting this technique, we designed the present study to make an animal model of NIDDM with hypertension. For this purpose, male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) as controls were used. As the results indicated, we found the unexpected and remarkable difference in the development of diabetes between two groups of rats. MATERIALS AND METHODS SHR were from an inbred colony that had been maintained in our laboratory since 1973, and WKY were purchased from Charles River Laboratories (Atsuki, Japan). The animals were bred in Specific Pathogen Free condition in Kyushu University Animal Center, where temperature (24OC), humidity (60%), and lighting (on 8 AM to 8 PM) were well-controlled. They had free access to tap water and standard chow diet, which contained carbohydrate in 5 1.6%,protein in 24.8%, minerals in 7.0%. fat in 4.4%. and cellulose in 3.5% (Clea Japan Inc. Tokyo). Two-day-old male SHR and WKY neonates were intraperitoneally injected through a 27-gauge microsyringe with STZ (Upjohn Co, Kalamazoo, MI) dissolved in 0.1 mol/L citrate buffer, pH 4.5. Doses of STZ given were varied as 37.5, 50.0, 62.5, and 75.0 mg/kg, but the injection volume was the same (4 rL/g body weight). Control rats received an equivalent amount of citrate buffer alone. The neonates were left with their own mother and weaned at 4 weeks of age.
From the Second Department of Internal Medicine, Fact&y of Medicine, Kyushu University, Fukuoka, Japan. Address reprint requests to Masanori Iwase, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-l-1, Higashi-ku. Fukuoka City, 812, Japan. o I987 by Grune & Stratton, Inc. 0026-0495/87/3607-0009$03.00~0 654
Body weight was measured weekly until the age of 12 weeks. Blood samples were obtained by cardiac puncture with a 28-gauge syringe at four and ten days of age, and by snipping the tail in a fed state (6 PM) after 3 weeks of age. Plasma glucose was measured by a Beckman Glucose Analyzer 2 (Beckman Instruments Inc, Fullerton, CA). At 12 weeks of age, both SHR and WKY, which received either vehicle or 75.0 mg/kg of STZ, were put into metabolic cages for 24 hours for a metabolic study. We measured one-day food and water intake, urine volume, and urinary glucose. At that time, a blood sample was taken as above mentioned and used for determination of glycosylated hemoglobin (GHb) by aminophenylboronic acid affinity chromatography (Isolab, Akron, OH). Blood pressure was measured in unanesthetized state by an indirect tail-cuff method at 11 or 12weeksofage. For statistical analysis, a two-tailed unpaired Student’s t-test was used. The result was considered to be significant when the P value was less than .05. RESULTS The serial changes of nonfasting plasma glucose level throughout the experimental course in SHR (Fig IA) and in
WKY (Fig 1B) received vehicle or 75.0 mg/kg of STZ at two days of age are demonstrated. Plasma glucose was elevated two days after the administration of STZ in either SHR or WKY. At ten days and 3 weeks of age, however, plasma glucose level in WKY fell and returned to the level of vehicle-treated control, while in SHR it fell but was still significantly higher than that in control. Thereafter, overt hyperglycemia gradually developed in SHR, while only mild hyperglycemia did in WKY. Figure 2 shows the relationship between STZ dose and plasma glucose level in SHR and WKY at 4 days, 10 days, and 12 weeks of age. At four days of age, ie, two days after STZ injection (Fig 2A), plasma glucose was elevated according to STZ dose given in both rats. Although the glycemic level was slightly higher in SHR than that in WKY, the difference did not reach the statistical significance at larger doses of STZ. The glycemic level in WKY treated with 50.0 mg/kg of STZ was comparable to that in SHR treated with 37.5 mg/kg of STZ. At ten days of age (Fig 2B), plasma glucose returned to the control level in WKY irrespective of the doses of STZ given, while in SHR it was above the control (vehicle-treated) level and was significantly higher than that in WKY. At 12 weeks of age (Fig 2C), plasma glucose was markedly and STZ dose-dependently elevated in Met&o/&n, Vol36, No 7 (July), 1987: op 654-657
NIDDM IN SHR AND WKY
655
..1
.
.
.
5HR
itreptozobcin /
Streptozobcin(mg/kg)
*,I-..
a
n=8
._*__“______*____--~-----_*_-----~
4
8
12
Age (weeks)
Fig 2. The relationship between doee of ST2 and nonfesting plasma glucose level at verioue ages in male SHB (a) and normotanstve WKY rats Cm given ST2 at two days, of age. The numbers of animaJa are 8 SHB and 9 WKY for vehicle. 10 and 6 for 37.6 mglkg STZ. 7 and 2 for BO.0 mglkg BTZ. 9 and 4 for 82.6 mglkg STZ. and Band 4 for 76.0 mglkg ST&treated group, reegectiveiy. *PC .06,**Pc .Ol, ?? **P.: .OOl BHR vWKY.Resuttsaremean + BEM. (AL 4 days; (B), 10 dqs: ICI. 12 weeks.
or Vehicle
n=4 n=9
1
4
I
8
12
Age (weeks) Fig 1. Changes in nonfasting plasma glucose level in (A) male 8HR and (B) normotensive WKY rets treated with vehide (-----I or at two days of age. ?? P < 76.0 mg/kg of streptozotocin (-1 .06, ?? *P d .Ol. ?? **P c .OOl v control. Results are mean f SEM.
SHR, while in WKY it remained at the control level. A clear difference was seen between SHR and WKY. As shown in Table 1, body weight at age 12 weeks was significantly smaller in SHR than that in WKY of vehicletreated control (P < .Ol), as well as STZ-treated groups. Body weight was reduced with dose of STZ given, such reduction being more marked in SHR. As shown in Table 2, GHb, food and water intakes, urine volume, and urinary glucose were markedly increased in SHR treated with 75.0 mg/kg of STZ compared to vehicletreated control. By contrast, these variables did not differ between vehicle- and STZ-treated groups in WKY, in which urinary glucose was not detected. There were no differences in systolic blood pressure between STZ-treated and control animals in either SHR or WKY. DISCUSSION
In the present study, the susceptibility to the development of NIDDM induced by neonatal STZ treatment was mark-
edly increased in SHR compared to WKY. Some factors could contribute to this clear difference. First, SHR may have glucose intolerance genetically because impaired glucose tolerance has been reported in SHR from 5 weeks of age: and also B cell mass of pancreatic islets was reduced by 50% in young SHR compared to normotensive Wistar rats of the same age.6 In the present results, however, nonfasting plasma glucose was substantially the same at any age between SHR and WKY of vehicle-treated group, and their GHb levels were also similar. Thus, genetically impaired glucose tolerance is unlikely in SHR. Second, SHR may be more sensitive to STZ than WKY in neonatal periods. In fact, plasma glucose at two days after STZ injection was higher in SHR than in WKY, although plasma glucose in WKY received 50.0 mg/kg and more of STZ was elevated to the comparable level to that in SHR received 37.5 or 50.0 mg/kg of STZ. It is unlikely that the changes of plasma glucose level after this initial hyperglycemia were affected by STZ itself because STZ has no long-acting effects on pancreatic islets.7 Therefore, the marked difference in the glycemic level at 12 weeks of age in this study could not be explained only by the mild difference in the sensitivity to STZ. Third, the regeneration capacity of B cells might account for the difference. It is interesting that WKY develop overt hyperglycemia by STZ treatment in adult’ but not in neonate. In the adult STZ model, persistent hyperglycemia and B cell necrosis occur immediately after STZ treatment. In the neonatal STZ model, however, the regeneration of B cell in pancreatic islets occurs after the insult of STZ, resulting in a recovery from an initial hyperglycemia.4 In this study, plasma glucose in WKY returned to the control level at ten days of age irrespective of the doses of STZ given, but in SHR it remained above the control level, suggesting that the regeneration of B cells could be sufficient in WKY but insufficient in SHR. As a result, reduced B cell mass in
IWASE ET AL
656
Table 1.
BodyWeight
of 12-Week-Old
SHR and Normotensive WKY Rats Given Vehicle or Various Doses of
Streptozotooin at Two Days of Age Streptcuotocin(me/kg)
SHR No.
10
8
Body weight (g)
9
9
203 + 4t
194 f 5t
7 214 ? 3.
249 4 6
248 + 8
75.0
62.5
50.0
37.5
Vehicle
WKY 5
9
No. Body weight (g)
4
4
247 f 5$
261 * 9+
2
271 j, 14
287 + 6
272
Values are mean f SEM. ?? P c .05 Y vehicla-treatedSHA or WKY. t P -c .OO 1 v vehicle-treated SHR or WKY. SP -c .Ol
v vehicle-treated SHR or WKY.
Table 2. Some Characteristics of 12-Week-Old
SHR and WKY Rats Given Vehicle or 75.0 mg/kg of ST2 at Two Days of Ago SHR
WKY
Vehicle
ST2
Vehicle
8
9
9
4
4.7 + 0.1
12.9 f 0.8*
5.0 t 0.4
5.6 + 0.5
No. Glycosylatedhemoglobin (%I
ST-Z
18.1 + 1.5
18.5 + 1.6
Water intake (mL/d)
38 + 3
106 f 8.
32 f 3
32 f 3
Urine volume (mL/d)
14 f 2
77 * 7f
13 * 2
12 t 2
Urinary glucose (g/d)
0
Food intake (g/d)
Systolic blood pressure (mm Hg)
18.4 + 1.7
208
28.9
+ l.l*
7.2 + 0.7’
f 5
206
+ 4
0 155 + 5
0 153 f 5
Results are mean f SEM. ?? P i
,001 Y vehicle-treated SHR.
SHR may lead to the exhaustion of B cells with lateoccurring severe hyperglycemia in adult periods. This interesting observation needs further study to be clarified for its mechanism. An increased insulin resistance is considered to be one of the pathogenetic mechanisms in the development of NIDDM in patients with hypertension because hyperinsulinemia has been demonstrated in oral glucose tolerance test? or postprandially9 in hypertensive patients. Such an increased insulin resistance could lead to a compensatory B cell regeneration and hyperplasia, and it may be speculated that diabetes becomes manifest when the regeneration of B cells cannot meet an increased insulin demand.” The genetically determined capacity for B cell regeneration has been shown from the studies of diabetic animal models such as diabetic
mouse,” diabetic Chinese hamster,‘* and diabetes after subtotal pancreatectomy in five strains of rats.13 Our present results suggest that this capacity is reduced in SHR compared to that in WKY. SHR, which were separated from WKY in 1963,” genetically develop spontaneous hypertension, and have been used worldwide as a model of human essential hypertension. Therefore, it might be interesting to take account of the capacity for B cell regeneration as well as an increased insulin resistance in patients with hypertension. In conclusion, male SHR and WKY were treated with various doses of STZ at two days of age and maintained for 12 weeks. As a result, only SHR developed NIDDM. The reduced capacity for B cell regeneration in SHR might account for this outstanding difference.
REFERENCES 1. Barrett-Connor
E, Criqui MH, Klauber MR, et al: Diabetes and hypertension in a community of older adults. Am J Epidemiol 113:276-284, 1981 2. Modan M, Halkin H, Almog S, et al: Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. J Clin Invest 75:809-817, 1985 3. Portha B, Picon L, Rosselin G, et al: Chemical diabetes in the adult rat as the spontaneous evolution of neonatal diabetes. Diabetologia 17:371-377, 1979 4. Bonner-Weir S, Trent DF, Honey RN, et al: Responses of neonatal rat islets to streptozotocin. Limited B-cell regeneration and hyperglycemia. Diabetes 30:64-69, 198 1 5. Yamori Y, Ohtaka M, Ueshima H, et al: Glucose tolerance in spontaneously hypertensive rats. Jpn Circ J 42:841-847, 1978
6. Postnov YV, Gorkova SI, Solovyova LP, et al: Reduction of B-cell component of pancreatic islets in spontaneously hypertensive rats. Virchows Arch 371:79-87, 1976 7. Bell RH Jr, Hye RJ: Animal models of diabetes mellitus, Physiology and pathology. J Surg Res 35:433-460, 1983 8. Somani P, Singh HP, Saini RK, et al: Streptozotocin-induced diabetes in the spontaneously hypertensive rat. Metabolism 28: 10751077,1979 9. Singer P, GiMicke W, Voigt S, et al: Postprandial hyperinsulinemia in patients with mild essential hypertension. Hypertension 7:182-186, 1985 10. Hellerstram C, Andersson A, Gunnarsson R, et al: Regeneration of islet cells. Acta Endocrinol 205:145-160, 1976 (suppl) 11. Coleman DL, Hummel KP: The influence of genetic back-
NIDDM IN SHR AND WKY
ground on the expression of the obese (ob) gene in the mouse. Diabetologia 9:287-293, 1973 12. Like AA, Gerritsen GC, Duhn WE, et al: Studies in the diabetic Chinese hamster: Light microscopy and autoradiography of pancreatic islets. Diabetologia 10:501-508,1974
657
13. Kaufmann F, Rodriguez RR: Subtotal pancreatectomy in five different rat strains. Incidence and course of development of diabetes. Diabetologia 27~38-43, 1984 14. Okamoto K, Aoki K: Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282-293, 1963