- Email: [email protected]
Diabetes, blood lipids, lipoproteins, and change of environment: Restudy of the “new immigrant Yemenites” in Israel
Diabetes,
Blood Lipids, Lipoproteins, and Change of Environment: Restudy of the “New Immigrant Yemenites” in Israel A. M. Cohen,
Restudy of 306 “new immigrant
J.
B. Cohen,
Fidel,
Yemenite”
Jews, an
ethnic group in which, upon their arrival in Israel, no diabetes
was detected,
immigration, higher
plasma
prevalence ance”)
to
of diabetes
male/female status-in
males
resulted
older
age
The
intoler-
and
9.7%
in increased
group
while only.
ratio was affected
underweight,
in males,
levels.
as “glucose
(13.2%
their
of diabetes and
in all age groups,
the
diabetic the
prevalent
(defined
in females
it affected
25 yr after
incidence
lipoprotein-lipid
11.8%
Obesity
prevalence males
and
of diabetes
rose
females).
revealed,
an increased
in
The
by weight
diabetes
was
in the overweight,
more
the rate of
diabetes in females equaled that of males. In nondiabetics
(those
with
neither
the
glucose
response
normal
glucose
tolerance
deteriorated
with
aging.
tolerance),
nor
the
Most
had a delayed insulin response.
However,
of nondiabetics
had insulin
and diabetics
insulin
diabetics about 50% response
peak at 60 min and similar insulin levels. It appears that in newly discovered population shortage
adult-onset
there is no shortage
diabetics in this
cholesterol
and triglycerides
the levels (TG)
were
TG. cholesterol,
higher when
tics, especially
and LDL-cholesterol
compared
in the group
Hyperlipoproteinemia
was
cholesterol
significantly
levels
hundred
and six Yemeni(es,
of overweight
ago and are living in six agricultural
diagnosed
males.
in 27.7%
of
In diabetics, the
diabetics.
I
N A SURVEY of Yemenite Jews carried out shortly after their arrival in Israel, it was found that the prevalence of diabetes was extremely low among “new immigrant Yemen-
About
65%75’%
in the study.
born in Yemen, immigrated of the settlers
willing and were examined.
to Israel 25 yr
settlements*
(Table
in each settlement
1).
were
Cases known to be diabetic or to
suffer from vascular disease were not included in the study. The subjects came to the examination blood was collected
determination
1 mg/ml
and in
studies, after which
following an overnight in heparin
disodium
i g glucose/kg
for glucose
EDTA
for lipid
body weight was given
and blood drawn after 30, 60, and 120 min in heparinized tubes for glucose and
insulin
determination.
history was taken and a physical examination Glucose analyzer
From the Diabetic Unit and the Isotope Laboratory for Endocrine Research and the Sh~mshon Family Mediea~ Center. &pat Holim Beit-Shemesh, ~epartrnent.~ of Inrernal Medicine A and B, Hadassah University Hospita! and Hebrew University. Hadassah Medical School. Jerusalem, Israel. Received for publication October I I, 1977. Supported by the United States-Israel &national Science Foundation Research Grant No. 804 and in part by the NIH Research Grant No. I ROI-AM-20733-01. Address reprint requests to Dr. A. M. Cohen, Head of Diabetic Unit, Hadassah Medical organization. Jerusalem, Israel. o I979 by Crune & Stratton, Inc. 0026-0495/79/2807.0002$02.00/0
182 maies and I24
females, aged 30 yr and over, are included
fast. Venous
716
METHODS
These Yemenites,
ratio was found to be reduced,
so in overweight
Three
AND
to those of nondiabe-
diabetics and 11 .O% of nondiabetics. HDL/LDL
MATERIALS
were
higher than levels upon their arrival. In diabetics. the plasma
ites.” whereas it was as high among old settled Yemenite Jews as among immigrants from Western countries.’ It has also been found that the rate of mortality from coronary artery disease among the “new ij~migrant Yemenites” was low in the first decade after their arrival in Israel but has increased during the following decade.’ During the last 2 yr, 18 yr after the first survey, we have reexamined the “new immigrant Yemenites” in Yemenite agricultural settlements around Jerusalem with the objective of finding out possible changes in the prevalence of diabetes compared with those of the initial survey and the plasma lipids and lipoproteins levels in nondiabetic and newly discovered diabetic Yemenites.
of insulin, but rather
of insulin action. in nondiabetics,
of plasma
A. Furst, and S. Eisenberg
was
determined
using
a
and insulin was determined
radioimmunoassay
using the Amersham
glucose tolerance test (CKiTT)
A
medical
made.
Beckman
glucose
by double-antibody Insulin Kit. An oral
was considered diabetic when
the blood glucose following the load was 2 I90 mg/ 100 ml at 60 min and 2 140 mgflO0
ml at 120 min. It was considered
normal when the blood glucose was G- I60 mg/ 100 m1 at 60 min and < 120 mg/ 100 ml at 120 min. Borderline cases were those with
blood glucose
values
between
189
and
160
mg/ 100 ml at 60 min and between I39 and I20 mg/ 100 ml at 120 min. Plasma lipids were studied in 289 subjects 116 females).
(169 males
For plasma lipid and lipoprotein
*The settlements are Bekoa. Givat-Yearim,
and
determina-
Ora. Shtulim,
Tarom. and Tzelafon.
Metabolism, Vol. 28, No. 7 (July), 1979
717
DIABETES. BLOOD LIPIDS, AND ENVIRONMENT
Table 1. Prevalence
of Diabetes
Underweight Borderline Examined
Age Groups Total
Overweight Diabetic
Number Age Group
in the Different
Borderline
Diabetic
Number N
%
N
%
Examined
Borderlnne
Diabetic
Number N
%
N
96
Examined
N
%
N
%
Males 30-44
35
1
2.9
2
6.7
26
2
7.7
2
7.7
61
3
4.9
4
6.6
45-55
21
3
14.3
3
14.3
24
3
12.5
3
12.5
45
6
13.3
6
13.3
55c
42
4
9.5
6
14.3
34
6
17.6
8
23.5
76
10
13.2
14
18.4
All ages
98
8
8.2
11
12.2
84
11
13.1
13
15.5
182
19
10.4
24
1 3.2
30-44
22
1
4.6
0
0
31
2
6.5
2
6.5
53
3
5.7
2
3.8
45-55
13
1
7.7
0
0
27
4
14.8
4
14.8
40
5
12.5
5
1 2.5
Females
55-c
13
2
15.4
1
7.7
18
4
22.2
5
27.6
31
6
19.5
6
19.5
All ages
48
4
8.3
1
2.1
76
10
13.2
11
14.5
124
14
11.3
12
9.7
306
33
10.8
36
1.8
Total for Males and Females Effect of obesity on prevalence of diabetes, for males x2 = 2.3520,
tion, plasma was separated within a few hours. The presence of a chylomicron layer was recorded by inspection of plasma stored at 4OC for 24 hr. Plasma lipid levels were determined by the autoanalyzer technique.3,4 HDL-cholesterol level was determined following he~rin-uncle precipitation of VLDL and LDL.* Paper electrophoresis of lipoproteins was performed as described by Lees and Hatch.6,’ LDL-cholesterol levels were calculated from the measured values of plasma cholesterol, plasma triglyceride, and HDL-cholesterol as described by Friedenwald et al.* The calculated LDL-cholesterol level was shown previously to reflect very accurately the true LDL-cholesterol level in an Israeli population examined by us in the Hadassah University Hospital.’ Hyperlipoproteinemia was defined by plasma and lipoprotein lipid levels following the WHO panel recommendations,“’ and using the cut-off criteria suggested by Fredrickson et al.” Accordingly, type IIA was diagnosed in subjects with LDL-cholesterol above 200 mg/lOO ml and normal plasma TG levels; type. IIB in subjects with elevations of both plasma TC and LDL-cholesterol levels; and type IV in subjects with plasma TG above 200 ml/ 100 ml and normal LDL-cholesterol. The more rare forms of hyperlipoproteinemia (types I, III, and V) were not encountered in the present study. According
to the ponderal
index (PI)-height
p NS kff = 1). for females x2 = 4.357 11 P c 0.02 (df = 1).
RESULTS
The percent of diabetic and borderline cases in the different age groups are shown in Table I. Of the total population, 11.8% were diabetic (13.2%
dq--
the subjects were subdivided into overweight and underweight groups. The “weighted average” PI for this population, assuming that all of them were at 100% normal relative weight,12 was 12.83 for males and 12.69 for females. Therefore, a similar PI was taken for both males and females as a cut-off point. In order to focus attention on the more overweight subjects, the cut-off point of 12.4 was chosen. Subjects with a PI of 12.4 and over were considered underweight, whereas those with a PI under 12.4 were considered overweight. The median PI for the total population was 12.488 + 0.550 for males and 12.179 r 0.388 for females. The insulin response curves were classified both in the diabetics and nondiabetics (according to the time of their maximal response-at 30, 60, or 120 min) as well as flat curves. Statistical evaluations were carried out using the Student t test and x*.‘~
Types of insulin and glucose response in underFig. 1. weight (PI > 12.4) and overweight (PI < 12.4) diabetic and nondiabetic Yemenites. Maximal insulin response at 30 min.
COHEN ET AL.
718
Types of insulin and glucose response in underFig. 2. weight (PI > 12.4) and overweight (PI < 12.4) diabetic and nondiabetic Yemenites. Maximal insulin response at 60 min.
Fig. 3. Types of insulin and glucose response in underweight (PI > 12.4) and overweight (PI < 12.4) diabetic and nondiabetic Yemenites. Maximal insulin response at 120 min.
of males and 9.7% of females) and 10.8% borderline cases (10.4% of males and 11.3% of females). The prevalence of diabetes increased with age in all age groups. Obesity resulted in an increase in the percent of diabetes in all the age groups for females, whereas in the male, obesity resulted in an increase of diabetes in the age group 55 + yr only. The effect of obesity on the prevalence of diabetes was not significant for males, but was significant for females, x2 = 4.35711, p < 0.05 (df = 1). The absolute blood glucose and plasma insulin
values at 0, 30, 60, and 120 min following the glucose load of the different types of insulin response curves with peaks at 30, 60, and 120 min are presented in Figs. l-3. The percent of the insulin response curves with peak at 30, 60, and 120 min as well as the flat curve in the nondiabetic and diabetic subjects is presented in Table 2. The change in insulin between the fasting level and that at 30, 60, and 120 min following the load in the different types of curves are presented in Table 3. In underweight nondiabetic subjects, about 39% of the cases had a
Table 2. Types of Insulin Response Following Oral Glucose Tolerance (%I Underweight
Overweight
Resqonsa Peaks
Response Peaks
Number Examined
Number 30 min
60 min
120 Ill,”
Flat
Examined
30 min
60 ml”
120 Ill,”
Flat
122
39.0
48.4
7.4
115
28.0
48.0
20.0
4.3
Borderline
12
8.3
50.0
25.0
16.7
21
0.0
42.9
47.6
9.5
Diabetic
12
8.3
50.0
25.0
16.7
24
8.3
50.0
33.3
8.3
Nondiabetic
Total
146
5.0
160
Nondiabetic
3
9.0
2
v. underweight,
vs. Nondiabetic,
SOverweiQht
tDiabetic
1.3
+ 2.0
t
f 3.7
t 3.1
+ 1.9
“corrected”
“corrected”
lZ G, + Ci= + GBO+ G,,i,.
6.0
3
NCXldiabetic
Diabetic
Flat
7.4
13.0
6
9.0
1.2
+ 2.27
8.0
9.4 f
12.8
Non *abetic
6
59
1
Fasting
Diabetic
120 min
Diabetic
Nondiabetic
60 min
Diabetic
47
With Peek
30 min
NUVlbW
Examined
Insulin Curve
5.8
28.0
29.8
34.6
35.5
17
0
k 3
+ 11.2
t
A 1.5
12.6
+ 1.5
+ 12.7
f
f 3.6
t 2.2
8.5
1 .o i- 2.0
0.4
48.0
54.5
4.7
8.6
8.0
120 ml”
of comparisons)
r 10.4
t 3.3
10
21 i. 2.7t
60 min
From Fasting Level
p x 4-number
+ 1.7
* 3
+ 7.0
f 5.2
+ 5.4
+ 2.6
p < 0.05.
p (“exact”
3.0
5.8
14.0
13.2
23.0
25.0
12.5
34 + 3.2f
30 min
lncnsse
Underweight
Table 3. Plasma Insulin Levels (Mean au/ml
<: 0.05.
1179
413
744
444
781
445
423
2 225t
* 23
* 53t
f 9
f 40’.
* 9.1
803
_+ 10.5$
min
GlUCOSEl*
O-120
Number
6.0 19.0
2
10.2
11.3
1.9
1.0
1.3
3
f 2.2t
+_ 2.0
f 2.8
f
12 *
11 t
152
12 f 2.5
Fasting
3
5
23
9
55
2
30
Examined
f 8.6
f 6.2$
5.0
+ 1.2
1.0 f 2.0
33.4
31.9
28 -t 4.0
38 2 3.7
93 f 21t
* 13.7
t 7.4
10
7.0
+ 0.4
1.3 -r 3.0
57.4
40.2
60 t
53 f 5.7$
67 i Ott
28 k 6.4
60 min
+ 3.0$
t 48$
zt 6.8
t f
12
11.4
6.0
t 2.3
1.7 ). 2.9
71.2
64.8
36 f: 5.7t
20.7
102.0
22.4
120 min
lncressa From Fasting Level
55 * S.lt.
30 min
Overweight
‘_ SE1 in Diabetics and Nondiabetics Following Oral Glucose Load
Glucose+
886
334
784
459
783
* 52t
+ 42
+ 40t
r 15
zt 44t
2 10
* 94t
885
484
+ 15
448
O-120min
COHEN ET AL.
720
maximum insulin response at 30 min, whereas in the diabetic subjects only 8.3% of the cases had a peak at 30 min. At 60 min, 48.4% of the nondiabetics and 50% of the diabetics had a peak. Of the diabetic subjects, 16.7% had a flat curve, versus 7.4% in the nondiabetic subjects. In the overweight category, 28% of the nondiabetic subjects and 8.3% of the diabetics had a maximum response curve at 30 min whereas 48% of the nondiabetics and 50% of the diabetics had a delayed response with peak at 60 min. There is no significant difference in the extent of insulin response of the nondiabetic and the diabetic in the corresponding types of curves (as multiple comparisons were made, the “exact” p was multiplied by 4, which is the number of comparisons in each instance) except for the 30-min peak curve of the underweight group (Table 3) and the 60-min values of the 30-min peak of the overweight group as well as the
different age groups vary inconsistently with age. In the several cases where the insulin values are lower in the older age group, the difference is not significant. In a large proportion of the overweight group, especially in males, the insulin values following the glucose load are significantly higher when compared to the corresponding underweight groups. Table 6 shows the ratio of the increase of blood glucose level from fasting levels to the corresponding increase of insulin values from fasting levels at 30, 60, and 120 min after the glucose load in the different types of insulin response curves. It is evident that the higher glucose insulin ratio in the diabetics at the different periods and in all types of insulin response curves are attributable to undue hyperglycemia, since insulin increments at these times were not different from those present in the normal glucose tolerance. The correlation index of plasma triglyceride. plasma cholesterol, and LDL- and HDL-cholesterol levels as related to age and sex in nondiabetic subjects is shown in Fig. 4. In both males and females the regression analysis (r) for the increase of total cholesterol and of LDL-cholesterol levels, with age, was signi~~nt, whereas for the TG level it was not significant. The regression analysis for the increase of‘ HDLcholesterol level, with age, was signihcant for females, but not for males. Mean plasma triglyceride, plasma cholesterol, LDLand HDL-cholesterol levels and HDL/LDL ratio are shown in Table 7. The mean plasma triglyceride was higher in overweight males and females as compared to underweight, but significant only in overweight nondiabeti~ males. Plasma cholesterol levels were in general higher in overweight as
120-min values of the 618min peak of the overweight group. The fasting insulin in the diabetics was not significantly different from that of the nondiabetics in the underweight group. In the overweight group, the fasting insulin of the diabetics was higher in the flat curves. Table 4 details the absolute blood glucose levels following OGTT in the underweight and overweight nondiabetic subjects in the different age groups. No difference due to aging was noted in the blood glucose values at 60 and 120 min following glucose load. It appears that females have lower blood glucose values than males, but the difference is not statistically significant. Table 5 details the insulin response following OGTT in the nondiabetic underweight and overweight subjects of the different age groups. It is apparent that the plasma insulin levels in the
Table 4. Glucose Tolerance Test in Nondiabetics of the Different Age Groups (Mean mg/lOO ml t SE) Overweight
Underweight
Ttme Followng
Tsme Following Glucose Load Exammed
0 in,”
Glucose Load
Numbw
Number Age Group
60 mm
120 min
Examined
0 min
60 mu?
120 ml”
30-44 MElie
32
86 + 1.5
110 i 2.9
86 t 2.4
22
86 I
1.8
118 t 3.7
94
Female
21
81 i- 2.0
110
t 3.2
90 f 3.5
27
86 ? 2.2
115 t 4.1
34 ? 3.1
+ 3.3
45-55 MaI@
15
87 t 2.3
125 t 4.4
65 f 3.8
18
86k22
131 12.2
92
f 3.6
FCllWle
12
87
116
c 6.7
86 + 5.3
19
83 ? 2.7
118
+ 4.5
95
r 3.5
Male
32
67 i 2.3
121 _i 2.9
82 + 3.1
20
so i 3.4
122
+ 4.9
95 f 4.3
Fi?m&e
10
64
117
87 f 5.0
9
85 t 2.5
I12
+ 6.6
96
i
1.9
55t
r 4.0
t 3.9
r42
Number
32
10
55+
15.0
11.9
t 3.6
i; 1.7
i 2.3
t 0.7’
t 1.2
t 1.2
39.0
23.0
30.0
29.0
27.2
+ 4.8
+ 3.4
+ 4.2
* 3.2
lr 6.0
i: 4.4
30 min
35.7
overweight, “corrected” p < 0.05.
12
*Underweight
21
30-44
45-55
Females
12.6
9.4
15
55+
9.8
32
12.6
Fasting
45-55
vs.
Examined
30-44
M&5
Ase GWJP
(Mean flu/ml
37.8
28.2
25.6
34.2
26.0
25.9
i 8.0
f 7.4
+ 3.0
k 4.2
-c 6.2
2 4.3
60 min
-
4.8
17.5
9.8
11.1
8.5
12.7
1.9
x 5.1
* 6.6
i
+ 2.0
+ 5.0
t 2.2
120 ml”
;t SE) in Nondiabetics
increase From Fasting Level
Underweight
Table 5. Plasma Insulin Response
9
19
27
20
18
22
Exammed
Number
in Different
11.4
9.9
10.7
15.9
17.0
12.9 1.4
1.3 + 1.7
f
i- 1.2
+ 5.8
+ 2.4t
i
Fasting
48.9
29.4
34.0
37.8
48.0
50.0
i
11.0
zt 8.0
r 4.8
i: 7.8
+ 7.2
+ 5.6
30 min
Overweight
32.3
25.0
34.8
38.0
56.2
46.4
* 8.0
2 5.2
t 4.4
+ 5.6
zt 8.0’
f. 4.9*
60 min
Increase From Fasting Level
Age Groups Following Oral Glucose Load
35.3
14.5
26.7
25.0
24.6
33.3
f 9.0.
A 3.9
f 3.9’
+ 10.0
e 6.3
* 6.7’
120 min
COHEN ET AL.
722
Table 6. Glucose/Insulin Time Following Glucose
Insulin response-peak
+ SE) in Nondiabetic,
Borderline,
and Diabetic Glucose Tolerance
Underweight
Load
(mini
Ratios (Mean
NondiabetIc at
Tests
Overweight
Borderline
Diabetic
Baderline
NondiabetIc
Diabetic
30 min
30
1.52
+ 0.17
3.94
5.06
1.14
t
1.40
18.9
t
10.8
60
1.52
+ 0.20
3.7
8.50
1.50
t: 0.47
30.4
i
12
? 0.94
3.8
9.33
0.20
+ 0.30
27.0
f; 6
120
-0.60
I?
48
insulin response-peak 30 60 120
+ 0.34
8.50
+z 3.9
24.5
r 2.12
2.76
-f 0.54
2.40
+ 0.6
5.7
i
4.60
r 2.8
8.5
f 0.92
1.04
* 0.22
1.40
t 0.3
2.9
f 0.6
+ 1.00
4.00
r
1.0
t 0.62
1.44
+ 0.72
3.5
59 at
1.6
6
+ 7.7
-0.7
6
55
9
r
1.1 1.0
12
120 min 4.87
60
PO.8
120
2
+ 0.23
30
”
32
1.54 -0.82
response-peak
1
2.25
n Insulin
1
at 60 min
-0.24 6
* 2.98
2.50
i: 0.80
47.0
+ 17.0
4.03
z+ 1.66
3.65
+ 0.73
4.80
t 8.74
+ 2.7
4.50
+ 2.6
11.6
c 4.8
1.48
i 0.44
3.30
+ 0.80
4.15
+ 0.82
zt 0.3
2.00
+ 1.2
3.08
+ 0.7 1
0.80
+ 0.1
0.88
3
3
compared to underweight subjects, but these differences were not statistically significant. Mean LDL-cholesterol was variable among the groups, and significantly higher in overweight diabetic males. Plasma HDL-cholesterol levels were in general lower in overweight subjects, but significant changes were noted only in nondiabetic males. Significant increases of mean blood lipid levels from nondiabetic through borderline and
23
_t 0.16 10
._
t 0.8 2
diabetic subjects were noted in the following measurements and categories: with plasma TG (underweight diabetic males and overweight diabetic females), plasma cholesterol (underweight diabetic males and overweight diabetic males), and plasma LDL-cholesterol (overweight diabetic males). The HDL/LDL cholesterol ratio was lower in overweight than in underweight subjects, significantly so only in the case of diabetics.
FEMALES
AGE ormfs~
3.1
n-c
yemenltes.
11
Diabetic
18.0
tp -c0.05,
-C 0.05,
13
Diabetic
lp
177
13
212
207
186
211
188
179
12.9.
+ 11.6’
+ 14.6
+ 4.4
t
k 16.0
+ 2.9
Plasma
3 5.0 18.0 7.3*t
t
140 133 I
1.3t
36 k 3.6
39 + 2.7
39 f
49 + 7.0
112 it 6.3
114
0.353
41 + 6.5
+ 0.038
t 0.02 + 0.06 + 0.005’t
0.372
0.289
r 0.050
+ 0.057
0.327
0.370
0.462
47 ? 1.9
126 rt. 13.7
HDL
113 * 3.5
LDL
HDL/LDL
Lipid Levels of Nondiabetic,
Cholesterol (mg/dl)
overweight vs. underweight of the respective group.
diabetic vs. nondiabetic within the PI group.
+ 36
f 31.0
136 f 8.0t
164
51
Nondiatwtic
128 + 9.5.
115 *
96 zt 5.3
(m&II
TG
Plasma
Borderline
Overweight
9
72
Examined
Bwderline
Nondiabetwz
Undwweight
Subiects
Number
Male
Table 7. Plasma and Lipoprotein
11
11
46
1
4
43
Examined
Number
Borderline,
f 6.5
135
+ 14.0.
117 + 17.0
101
103
81 + 12.0
SO f 3.6
(mg/dl)
TG
PlaSma
and Diabetic
183
199
227
194
183
11.3
+ 7.5
r 10.3
A 5.0
199
f
f 4.1
12.2
f 5.3
133
f
134
+ 10.4
138 f 9.6
137
122
124 f 4.8
LDL
Cholesterol
t SE)
Female
(Mean
Plasma
Subjects
0.341 0.275
47 f 2.3 35 a 3.7
42 + 1.6
0.328
0.387 45
0.368 44 t 3.3
k 0.514.
k 0.003
-r 0.019
0.338
f 0.057
k 0.022
HM/LDL
43 f 2.4
HDL
hng/dl)
E
P
724
COHEN ET AL.
Table 8. Incidence of Hyperlipoproteinemia Diabetic,
(%I Among
Nondiabetic.
Borderline
and Diabetic Subjects
Subject
Examned
IIA
IIB
219
2.3 15)’
0.9 (21
LipoproteinType
Number
Nondiabetic
IV
7.7 (17)
Borderline
31
6.4 (2)
3.2 (1)
12.9 (4)
Diabetic
36
11.1 (41
2.8 (1)
13.9 (5)
67
9.0 (6)
3.0 (2)
13.4 (9) .-I__
esting to note that in diabetic subjects with hyperlipoproteinemia, the HDL/LDL cholesterol ratio was lower than in nondiabetics with comparable lipoprotein profiles. These differences are significant for type 1la and I lb. DISCUSSION
Diabetic IBorderline ‘Number
in parentheses represents number of subjects with
specified lipoprotein type. x2 nondiabettc vs. diabetic = 9.5472.
p c 0.05 (df -= 1).
x2 Nondlabetvz vs. borderline = 5.3424,
p. NS Idf = 1).
The incidence of hyperlipoproteinemia in nondiabetic, borderline, and diabetic subjects is shown in Table 8. it is evident that in diabetic subjects, all three types of hyperlipoproteinemia were more common than in nondiabetic subjects. We are aware of the small number of cases of diabetics, but we still calculated the x?: nondiabetic versus diabetic = 9.5472, p -: 0.05 (df = I ). Mean plasma lipid and lipoprotein levels of subjects with normal lipoprotein profile and the three types of hyperlipoproteinemia encountered in the study population are shown in Table 9. As expected, LDL-cholesterol levels were elevated in subjects with types Ila and Ilb and TG was elevated in types Ilb and IV when comparing hyperlipoproteinemic subjects to those with normal lipoprotein pattern, either in the nondiabetic, borderline, or diabetic subjects. It is inter-
Table 9. Plasma and Lipoprotein
of Diabetes
Our diagnostic
criteria for diabetes meliitus based on both a I-hr value of 190 mg/IOO ml and a 2-hr value of 140 mg/ 100 ml glucose following an oral glucose load satisfy the commonly used criteria.14.‘” This abnormal glucose tolerance test indicates “chemical and not necessarily “clinical diadiabetes” betes”.” The percent of maturity-onset diabetes in the examined population is 11.X% (I 3.3% in males and 9.7% in females). These results arc not different from those observed in other studies outside Israel.” ” The present results confirm our previous observations’ that on changing the environment, this population, in which almost no diabetes was detected 20 yr ago. now has a prevalence of diabetes comparable to other affluent communities. The incidence of maturity-onset diabetes increased with age and was higher in individuals who were overweight. In spite of the small number of cases, WC calculated the x’. which is significant for overweight females, but not for males. This is in accordance with the known fact
Lipid Level Among Subjects With Normal Lipoprotein Hyperlipoproteinemia
Llpoproteln Pattern
Prevalence
(Mean
Cholesterol
TG
Plasma
Profile and With
i SE1 lmgidl)
LOL
HDL
--_-HDL/LDL
NondiabetIc 88 t 2.7
175 f 2.0
114 t 1.9
IIA (5)
Normal (195)’
101 1? 11.1
274 i- 3.1
232 -t 10.0
IIB (2)
242 I 4.5
317 -t 16.5
243 f 11.5
IV (17)
273 + 15.6
205 i 6.7
102 + 7.1
44 1- 1.0 44.6
0.386
f 0.008
f 3.2
0.257
-r 0.027
36 * 0.5
0.176
? 0.1
0.340
f 0.023
0.362
i 0.035
35.2
+ 2.1
Borderline Normal 124) IIA 121 flB (1) IV (4) Diabetic
89 + 6.7 131 -r 27 203 461 + 129
177 i 7.0
116 ?r 5.7
42 5 3.6
289 + 11.5
221 * 4.0
41 +6
289 244 ?: 43
214
35
0.1829
i 0.03
0.1636
108 r 20
59 t- 13
0.458
Normal (26)
116 +8t
187 t 6.0
122 15.7
41 -c 3.3
0.3515
IIA (4)
122 * 34
301 + 23.7
226 + 12.6
35 t 0.5
0.182
IIB (1)
250
284
IV 151
310 ” 66.9
209 rt 18.2
*Number in parentheses represents number of subjects. tNondiabetic vs. diabetic p --c0.05.
219 131 k 8
29 36 i; 5.3
t 0.10 2 0.037 + 0.004t
0.132 0.2666
.k 0.028
DIABETES, BLOOD LIPIDS, AND ENVIRONMENT
that obesity significantly alters glucose tolerance.*’ It is noteworthy that in this population the effect of obesity on the prevalence of diabetes was more pronounced in females than in males. While the effect of overweight versus underweight on the increase in the prevalence of diabetes in males was observed in the older age group only, in females its expression was significant and evident in the younger age groups as well. It remains to be seen whether obesity is the primary cause for the increased prevalence of diabetes or if it accompanies diabetes as part of the metabolic changes that have occurred in this population on changing their environment, since in males there was a pronounced increase in the prevalence of diabetes in the underweight group as well. The prevalence of maturity-onset diabetes in males was higher than in females in the underweight group, whereas in the overweight group the prevalence in females almost equaled that of males. This higher diabetic male/female ratio was also observed in our previous survey among the old settled Yemenites’ and in other populations.“-24 The role of obesity in the change of this ratio observed in the present study may explain the changing sex incidence of diabetes that was observed in recent decades in the “developed countries” where an increase of diabetes among females was found in all age groups.‘~ “-*’ Several authors reported an initially delayed insulin response to hyperglycemia as a common feature to all forms of maturity-onset diabetes mellitus from prediabetes,28,29 the mildest forrns30 and the clinical overt disease.“-33 However, other investigators have reported identical or greater insulin response to intravenous or oral glucose in diabetic subjects, obese or nonobese, than in nondiabetics of comparable age, height, and weight.“, 34-36 We have therefore classified, both in the nondiabetics and diabetics, the insulin response curves according to the time of the maximal peak. It is apparent that in maturity-onset diabetics 91.7% of the underweight and 91.7% of the overweight have delayed insulin responses. It is noteworthy that among the nondiabetics, 53.4% of the underweight and 68% of the overweight also have delayed insulin responses with peaks at 60 or 120 min following the glucose load. However, the extent of the insulin responses of the diabetics, at all times, in the
725
corresponding types of insulin curves are not significantly different from the nondiabetics except for the cases with the 30-min maximal responses. The higher glucose/insulin ratio in the diabetics at the different periods of time, except for the flat curve responses, is attributable to undue hyperglycemia, since insulin increments at those times were not different from those present in the normal glucose tolerance. In conformity with other studies,37.3X our results indicate no significant difference in the fasting insulin levels between maturity-onset diabetics and nondiabetics in the underweight group. In the overweight group the fasting insulin level of diabetics with a flat curve are higher than the respective nondiabetic groups, as reported by Karam et al.39 Thus, in the early stages of adult-onset diabetes the fasting insulin and the insulin response is not different from that of the nondiabetic controls. It has been reported by some40.4’ that with advancing age there is deterioration of the mean glucose tolerance. However, our results are in accordance with other observers’B,4’,J’ who did not find any deterioration of glucose tolerance with age in nondiabetic individuals (i.e., those with normal glucose tolerance). Insulin release following glucose stimulation was also reported by some authors44,45 to deteriorate with age. Our results in the nondiabetics do not show any consistent pattern of change in the insulin response with advancing age, in conformity with the reports of other investigators 42.46 48 In the diabetic glucose tolerance curves, the ratio of glucose insulin increment from fasting level at 30, 60, and 120 min are higher than in the nondiabetic. This is attributable to undue hyperglycemia, since insulin increments at these times equaled those present in normal glucose tolerance, both in underweight and overweight subjects, except for the flat curves. It appears that in order to explain this fact one has to resort to “insulin resistance” or imply that the insulin molecule itself is structurally not intact. Obesity is frequently cited as a cause of insulin ineffectiveness, but this ineffectiveness was also evident in our nonobese diabetics. The maturity-onset diabetes mellitus, even in its early stages, is often defined as undue hyperglycemia resulting from a shortage of insulin. Our results cannot support this view. They
726
COHEN ET AL.
suggest rather that there is a shortage of insulin action. flood Lipids in ~o~diub~tic ~ubj~et~
Plasma cholesterol and LDL-cholesterol levels were significantly lower in the nondiabetic Yemenite settler described here compared to the non-Yemenites reported recently by Eisenberg’ and Klorfajn et a1.49(Table lo), whereas HDLcholesterol and plasma TG levels did not differ. However, the non-Yemenites were not screened for impairment of glucose tolerance and represented an urban population. The plasma cholesterol level in the non-diabetic Yemenite settlers now living in Israel for 25 yr is higher than levels found soon after their arrival in Israel, as reported by Toor et aL5’ and Brunner and Lobl.5’ In our nondiabetic population, the regression analysis did reveal a significant increase of total cholesterol and LDL-cholestero1 levels with age, whereas there was no such trend for an increase of plasma TG levels. This is in conformity with several authors52353who reported an increase of the blood cholesterol level with age in both males and females. Other investigators report no change with age.49.s4Obesity resulted in significant increases of plasma TG levels and decreased HDL-cholesterol levels in males but not females. Blood Lipids in diabetic Subjects
Plasma TG was increased in the diabetics, both male and female. The LDL-cholesterol was increased in males while no consistent trend was noted in the HDL-cholesterol levels. Higher prevalence of hyperli~mia among diabetic subjects as compared to nondiabetics was reported by several investigators.55--59Simi-
larly, in this unique Yemenite population in Israel, the incidence of hyperlipoproteinemia among the diabetics was more than twice that of nondia~ti~s, 27.7% and 1.096, respectively, whereas the per cent of subjects with different types of hyperlipoproteinemia was similar to that reported by other investigators.56-59These observations, together with those already discussed herein, indicate that in the Yemenite population an increase of plasma Iipid levels occurred during the 25 yr following immigration to Israel, most probably due to the changing environmental conditions. However, the expression of diabetes in this unique population, at least as related to the plasma lipid and lipoprotein levels, was similar to that of other non-Yemenite diabetic populations. The present study is the first investigation in Israel in which plasma HDL-cholesterol levels were determined in diabetic and nondiabetic subjects of one ethnic group living under similar environmental conditions. Clinical and epidemiologic studies show a consistent negative correlation between absolute plasma HDL concentration and coronary risk.60-62It has been postulated6’ that the “protective” effect of HDL may relate to the role of HDL in the removal of cholesterol from peripheral tissues.63.64Carew et alS6j suggest that raised HDL concentrations may limit the uptake by smooth muscle of the arterial wall of LDL, a lipoprotein that contributes to the initiation and progression of atherogenie lesions. The decisive factor in coronary risk is the relative HDL/LDL ratio at any given LDL concentration.b’.62 Our data (Table 7) suggests that in the underweight man and woman, HDLjLDL ratio is not affected by diabetes, while diabetes in the overweight male and female results in a decreased HDL/LDL ratio.
Table 10. Plasma Lipids and Cholesterol Levels in Yemenites and Non-Yemenites With Normal Lipoprotein Profile (Mean f SE) Cholesterol (mg/d~) Group
Nondiabetic Yemenites
NUmbar
Plasma TG
Examswd
fmgid4
219
105 + 2.7’
185 r 2.0
121 * 1.9
43 * 1.0
65
104 t 4.1
208 + 4.lt
139 + 2.q
44 + 2.1
386
112 + 2.6
227 * 2.1t
-
-
Plasma
LDL
HDL
Non-Yemenites (Eisenberg? Non-Yemenites (Klorfajn et al.“)
lt
= mean + SE.
tp < 0.01 Yemenites vs. non-Yemenites.
727
DIABETES, BLOOD LIPIDS, AND ENVIRONMENT
REFERENCES I. Cohen AM: Prevalence of diabetes among different ethnic Jewish groups in Israel. Metabolism 1050, 1961 2. Cohen AM, Eisenberg S: Ischemic heart disease in Israel. Cardiology Today 2 (3):7, 1974 3. New York Technicon Corporation: Autoanalyzer Methodology Manual N-24a. 1965 4. New York Technicon Corporation: Autoanalyzer Methodology Manual N-78. 1968 5. Burstein M, Samille J: Sur un dosage rapid du cholesterol lit aux a et aux @ lipoproteins du serum. Clin Chim Acta 5609, 1960 6. Lees RS, Hatch FT: Sharper separation of lipoprotein species by paper electrophoresis in albumin-containing buffer. J Lab Clin Med 61518, 1963 7. Hatch FT, Lees RS: Practical methods for plasma lipoprotein analysis. Adv Lipid Res 6:4, 1968 8. Friedenwald WT. Levy RI, Fredrickson DS: Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499, 1972 9. Eisenberg S: Typing of hyperlipoproteinemia in an Israel hospital. Isr J Med Sci 12: 126 I, 1976 IO. Beaumont JL, Carlson LA, Cooper CR, et al; Memoranda: Classification of hyperlipidemias and hyperlipoproteinaemias. Bull WHO 43:891, 1970 I I. Fredrickson DS, Levy RI: Familial hyperlipoproteinemia, in Stanburg JB, Wyngaarden JB, Fredrickson DS (eds): The Metabolic Basis of Inherited Disease (ed 3). New York, McGraw-Hill, 1972, p. 545 12. Society of Actuaries: Build and Blood Pressure Study, vol I. Chicago, The Society, 1959 13. Nie NH, Hull CH, Jenkins JG, et al: Statistical Package for the Social Sciences. McGraw-Hill New York, 1970 14. Fajans SS, Conn JW: Prediabetes, subclinical diabetes and latent diabetes: Interpretation, diagnosis and treatment, in Liebel BS and Wrenshaw GA (eds): On the Nature and Treatment of Diabetes. Amsterdam, Excerpta Medica Foundation, 1965, p 641 IS. Committee on Statistics of the American Diabetes Association: Standardization of the oral glucose tolerance test. Diabetes 18:299, 1969 16. Fajans SS: Tha natural history of idiopathic diabetes mellitus. Heterogeneity of insulin response in latent diabetes, in Creutzfeldt W, Kijbberling J, Neel JV (eds): The Genetics of Diabetes Mellitus. New York, Springer-Verlag, 1976. pp 64-78 17. Crombie DL: Incidence of glycosuria and diabetes. Proc R Sot Med 55:205,1962 18. Butterfield WJH: Summary of results of the Bedford diabetic survey. Proc R Sot Med 57:196, 1964 19. Genuth SM, Hauser HB, Carter JR Jr, et al: Community screening for diabetes by blood glucose measurement. Diabetes 25: I 110, 1976 20. West KM, Kalbfleisch JM: Glucose tolerance, nutrition and diabetes in Uruguay, Venezuela, Malaya and East Pakistan. Diabetes l5:9, 1966 21. Wilkerson HLC, Krall LP: Diabetes in a New England town: A study of 3516 persons in Oxford, Mass. JAMA 135:209,1947
22. Freedman LR, Blackard WC, Sagan LA, et al: The epidemiology of diabetes mellitus in Hiroshima and Nagasaki. Yale J Biol Med 37:283, 1965 23. Malins JM, Fitzgerald ME, Wall M: A change in the sex incidence of diabetes mellitus. Diabetologia I I2 I965
728
43. Dud1 J, Ensinck JW: Insulin and glucagon relationship during aging in man. Meta~lism 26:33, 1977 44. Crockford PM, Harbeck RJ, Williams RH: Influence of age on intravenous glucose tolerance and serum immunoreactive insulin. Lancet I :465, 1966 45. Barbagallo-Saugiorgi G, Ludicina E, Bompiani CD, et al: The pancreatic beta-cell response to intravenous administration of glucose in elderly subjects. J Am Geriatr Sot 18:529, 1970 46. O’Sullivan JB, Mahan CM, Freedlander AE, et al: Effect of age on carbohydrate metabolism. J Clin Endocrinol Metab 33:619, 1971 47. Streeten DHP, Gerstein MM. Marmor BM, et al: Reduced glucose tolerance in elderly human subjects. Diabetes 14:579, I965 48. Zentinogen IY, Cherondache CN, Pincus G: The process of aging: Serum glucose and immunoinsulin levels during oral glucose tolerance tests. J Am Geriatr Sot 17:i. 1969 49. Klorfajn I, Mizrahy 0. Assa S. et al: The blood level of lipid ingredients in the elderly. Harefuah 92106, 1977 50. Toor M, Katchalsky A, Agmon J, et al: Serum lipids and atherosclerosis among Yemenite immigrants in Israel. Lancet 1:1270, 1957 51. Brunner D, Lob1 K: Serum cholesterol, electrophoretie lipid pattern, diet and coronary artery disease: A study in coronary patients and in healthy men of different origin and occupation in Israel. Ann Intern Med 49:732, 1958 52. Lewis LA, Olmsted F, Page IH. et al: Serum lipid levels in normal persons. Findings of a cooperative study of lipoproteins and atherosclerosis. Circulation 16:227. 1957 53. Marmorston J, Griffith CC. Geller PJ, et al: Urinary steroids in the measurement of aging and of atherosclerosis. J Am Geriatr Sot 23:48 I, 1975
COHEN ET AL.
54. Hays D. Neil1 DW: Serum cholesterol and triglycerides in ischemic heart disease. Clin Sci Mol Med 26:185, 1964 55. Bergquist N: Serum lipids in ambulatory diabetic clientele. Acta Med Stand 187:213, 1970 56. Wilson DE, Schreibman PH. Arky R: Hyperlipidemia in an adult diabetic population. J Chronic Dis 23501, 1970 57. Leren P, Haabrekke 0: Blood lipids in normals. Acta MedScand 189:501, 1971 58. Wood PDS, Stern MP. Silvers A. et al: Prevalence of plasma lipoprotein abnormalities in a free-living ~pulation of the Central Valley. California. Circulation 45:114, 1972 59. Schonfeld G, Birge C. Miller JP, et al: Apolipoprotein-B levels and altered lipoprotein composition in diabetes. Diabetes 23:827. 1974 60. Berg K, B@resen AL: Serum-high-density-lipoprotein and atherosclerotic heart disease. Lancet 1:499, 1976 61. Miller GJ, Miller NE: Plasma-high-density-lipoprotein concentration and development of ischemic heart disease. Lancet I : 16, 197.5 62. Rhoads GG. Gulbrandsen CL, Kagan A: Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. N Engl J Med 294:293. 1976 63. Stein Y, Stein 0: High density lipoproteins reduce the uptake of low density lipoproteins by human endothelial ceils in culture. Biochem Biophys Acta 431:363, 1976 64. Miller NE, Weinstein DB, Steinberg D: Metabolism uf human lipoproteins, high density (HDL) and low density (LDL) of ~brobiasts of normal and of homozygous familial hyper~holesterolemic (FH) subjects. Clin Res 24:459 A, 1976 6s. Carew TE, Koschinsk T, Hayes SB, et al: A mechnnism by which high density lipoproteins may slow the atherogenic process. Lancet I : I3 15, 1976
Blood Lipids, Lipoproteins, and Change of Environment: Restudy of the “New Immigrant Yemenites” in Israel A. M. Cohen,
Restudy of 306 “new immigrant
J.
B. Cohen,
Fidel,
Yemenite”
Jews, an
ethnic group in which, upon their arrival in Israel, no diabetes
was detected,
immigration, higher
plasma
prevalence ance”)
to
of diabetes
male/female status-in
males
resulted
older
age
The
intoler-
and
9.7%
in increased
group
while only.
ratio was affected
underweight,
in males,
levels.
as “glucose
(13.2%
their
of diabetes and
in all age groups,
the
diabetic the
prevalent
(defined
in females
it affected
25 yr after
incidence
lipoprotein-lipid
11.8%
Obesity
prevalence males
and
of diabetes
rose
females).
revealed,
an increased
in
The
by weight
diabetes
was
in the overweight,
more
the rate of
diabetes in females equaled that of males. In nondiabetics
(those
with
neither
the
glucose
response
normal
glucose
tolerance
deteriorated
with
aging.
tolerance),
nor
the
Most
had a delayed insulin response.
However,
of nondiabetics
had insulin
and diabetics
insulin
diabetics about 50% response
peak at 60 min and similar insulin levels. It appears that in newly discovered population shortage
adult-onset
there is no shortage
diabetics in this
cholesterol
and triglycerides
the levels (TG)
were
TG. cholesterol,
higher when
tics, especially
and LDL-cholesterol
compared
in the group
Hyperlipoproteinemia
was
cholesterol
significantly
levels
hundred
and six Yemeni(es,
of overweight
ago and are living in six agricultural
diagnosed
males.
in 27.7%
of
In diabetics, the
diabetics.
I
N A SURVEY of Yemenite Jews carried out shortly after their arrival in Israel, it was found that the prevalence of diabetes was extremely low among “new immigrant Yemen-
About
65%75’%
in the study.
born in Yemen, immigrated of the settlers
willing and were examined.
to Israel 25 yr
settlements*
(Table
in each settlement
1).
were
Cases known to be diabetic or to
suffer from vascular disease were not included in the study. The subjects came to the examination blood was collected
determination
1 mg/ml
and in
studies, after which
following an overnight in heparin
disodium
i g glucose/kg
for glucose
EDTA
for lipid
body weight was given
and blood drawn after 30, 60, and 120 min in heparinized tubes for glucose and
insulin
determination.
history was taken and a physical examination Glucose analyzer
From the Diabetic Unit and the Isotope Laboratory for Endocrine Research and the Sh~mshon Family Mediea~ Center. &pat Holim Beit-Shemesh, ~epartrnent.~ of Inrernal Medicine A and B, Hadassah University Hospita! and Hebrew University. Hadassah Medical School. Jerusalem, Israel. Received for publication October I I, 1977. Supported by the United States-Israel &national Science Foundation Research Grant No. 804 and in part by the NIH Research Grant No. I ROI-AM-20733-01. Address reprint requests to Dr. A. M. Cohen, Head of Diabetic Unit, Hadassah Medical organization. Jerusalem, Israel. o I979 by Crune & Stratton, Inc. 0026-0495/79/2807.0002$02.00/0
182 maies and I24
females, aged 30 yr and over, are included
fast. Venous
716
METHODS
These Yemenites,
ratio was found to be reduced,
so in overweight
Three
AND
to those of nondiabe-
diabetics and 11 .O% of nondiabetics. HDL/LDL
MATERIALS
were
higher than levels upon their arrival. In diabetics. the plasma
ites.” whereas it was as high among old settled Yemenite Jews as among immigrants from Western countries.’ It has also been found that the rate of mortality from coronary artery disease among the “new ij~migrant Yemenites” was low in the first decade after their arrival in Israel but has increased during the following decade.’ During the last 2 yr, 18 yr after the first survey, we have reexamined the “new immigrant Yemenites” in Yemenite agricultural settlements around Jerusalem with the objective of finding out possible changes in the prevalence of diabetes compared with those of the initial survey and the plasma lipids and lipoproteins levels in nondiabetic and newly discovered diabetic Yemenites.
of insulin, but rather
of insulin action. in nondiabetics,
of plasma
A. Furst, and S. Eisenberg
was
determined
using
a
and insulin was determined
radioimmunoassay
using the Amersham
glucose tolerance test (CKiTT)
A
medical
made.
Beckman
glucose
by double-antibody Insulin Kit. An oral
was considered diabetic when
the blood glucose following the load was 2 I90 mg/ 100 ml at 60 min and 2 140 mgflO0
ml at 120 min. It was considered
normal when the blood glucose was G- I60 mg/ 100 m1 at 60 min and < 120 mg/ 100 ml at 120 min. Borderline cases were those with
blood glucose
values
between
189
and
160
mg/ 100 ml at 60 min and between I39 and I20 mg/ 100 ml at 120 min. Plasma lipids were studied in 289 subjects 116 females).
(169 males
For plasma lipid and lipoprotein
*The settlements are Bekoa. Givat-Yearim,
and
determina-
Ora. Shtulim,
Tarom. and Tzelafon.
Metabolism, Vol. 28, No. 7 (July), 1979
717
DIABETES. BLOOD LIPIDS, AND ENVIRONMENT
Table 1. Prevalence
of Diabetes
Underweight Borderline Examined
Age Groups Total
Overweight Diabetic
Number Age Group
in the Different
Borderline
Diabetic
Number N
%
N
%
Examined
Borderlnne
Diabetic
Number N
%
N
96
Examined
N
%
N
%
Males 30-44
35
1
2.9
2
6.7
26
2
7.7
2
7.7
61
3
4.9
4
6.6
45-55
21
3
14.3
3
14.3
24
3
12.5
3
12.5
45
6
13.3
6
13.3
55c
42
4
9.5
6
14.3
34
6
17.6
8
23.5
76
10
13.2
14
18.4
All ages
98
8
8.2
11
12.2
84
11
13.1
13
15.5
182
19
10.4
24
1 3.2
30-44
22
1
4.6
0
0
31
2
6.5
2
6.5
53
3
5.7
2
3.8
45-55
13
1
7.7
0
0
27
4
14.8
4
14.8
40
5
12.5
5
1 2.5
Females
55-c
13
2
15.4
1
7.7
18
4
22.2
5
27.6
31
6
19.5
6
19.5
All ages
48
4
8.3
1
2.1
76
10
13.2
11
14.5
124
14
11.3
12
9.7
306
33
10.8
36
1.8
Total for Males and Females Effect of obesity on prevalence of diabetes, for males x2 = 2.3520,
tion, plasma was separated within a few hours. The presence of a chylomicron layer was recorded by inspection of plasma stored at 4OC for 24 hr. Plasma lipid levels were determined by the autoanalyzer technique.3,4 HDL-cholesterol level was determined following he~rin-uncle precipitation of VLDL and LDL.* Paper electrophoresis of lipoproteins was performed as described by Lees and Hatch.6,’ LDL-cholesterol levels were calculated from the measured values of plasma cholesterol, plasma triglyceride, and HDL-cholesterol as described by Friedenwald et al.* The calculated LDL-cholesterol level was shown previously to reflect very accurately the true LDL-cholesterol level in an Israeli population examined by us in the Hadassah University Hospital.’ Hyperlipoproteinemia was defined by plasma and lipoprotein lipid levels following the WHO panel recommendations,“’ and using the cut-off criteria suggested by Fredrickson et al.” Accordingly, type IIA was diagnosed in subjects with LDL-cholesterol above 200 mg/lOO ml and normal plasma TG levels; type. IIB in subjects with elevations of both plasma TC and LDL-cholesterol levels; and type IV in subjects with plasma TG above 200 ml/ 100 ml and normal LDL-cholesterol. The more rare forms of hyperlipoproteinemia (types I, III, and V) were not encountered in the present study. According
to the ponderal
index (PI)-height
p NS kff = 1). for females x2 = 4.357 11 P c 0.02 (df = 1).
RESULTS
The percent of diabetic and borderline cases in the different age groups are shown in Table I. Of the total population, 11.8% were diabetic (13.2%
dq--
the subjects were subdivided into overweight and underweight groups. The “weighted average” PI for this population, assuming that all of them were at 100% normal relative weight,12 was 12.83 for males and 12.69 for females. Therefore, a similar PI was taken for both males and females as a cut-off point. In order to focus attention on the more overweight subjects, the cut-off point of 12.4 was chosen. Subjects with a PI of 12.4 and over were considered underweight, whereas those with a PI under 12.4 were considered overweight. The median PI for the total population was 12.488 + 0.550 for males and 12.179 r 0.388 for females. The insulin response curves were classified both in the diabetics and nondiabetics (according to the time of their maximal response-at 30, 60, or 120 min) as well as flat curves. Statistical evaluations were carried out using the Student t test and x*.‘~
Types of insulin and glucose response in underFig. 1. weight (PI > 12.4) and overweight (PI < 12.4) diabetic and nondiabetic Yemenites. Maximal insulin response at 30 min.
COHEN ET AL.
718
Types of insulin and glucose response in underFig. 2. weight (PI > 12.4) and overweight (PI < 12.4) diabetic and nondiabetic Yemenites. Maximal insulin response at 60 min.
Fig. 3. Types of insulin and glucose response in underweight (PI > 12.4) and overweight (PI < 12.4) diabetic and nondiabetic Yemenites. Maximal insulin response at 120 min.
of males and 9.7% of females) and 10.8% borderline cases (10.4% of males and 11.3% of females). The prevalence of diabetes increased with age in all age groups. Obesity resulted in an increase in the percent of diabetes in all the age groups for females, whereas in the male, obesity resulted in an increase of diabetes in the age group 55 + yr only. The effect of obesity on the prevalence of diabetes was not significant for males, but was significant for females, x2 = 4.35711, p < 0.05 (df = 1). The absolute blood glucose and plasma insulin
values at 0, 30, 60, and 120 min following the glucose load of the different types of insulin response curves with peaks at 30, 60, and 120 min are presented in Figs. l-3. The percent of the insulin response curves with peak at 30, 60, and 120 min as well as the flat curve in the nondiabetic and diabetic subjects is presented in Table 2. The change in insulin between the fasting level and that at 30, 60, and 120 min following the load in the different types of curves are presented in Table 3. In underweight nondiabetic subjects, about 39% of the cases had a
Table 2. Types of Insulin Response Following Oral Glucose Tolerance (%I Underweight
Overweight
Resqonsa Peaks
Response Peaks
Number Examined
Number 30 min
60 min
120 Ill,”
Flat
Examined
30 min
60 ml”
120 Ill,”
Flat
122
39.0
48.4
7.4
115
28.0
48.0
20.0
4.3
Borderline
12
8.3
50.0
25.0
16.7
21
0.0
42.9
47.6
9.5
Diabetic
12
8.3
50.0
25.0
16.7
24
8.3
50.0
33.3
8.3
Nondiabetic
Total
146
5.0
160
Nondiabetic
3
9.0
2
v. underweight,
vs. Nondiabetic,
SOverweiQht
tDiabetic
1.3
+ 2.0
t
f 3.7
t 3.1
+ 1.9
“corrected”
“corrected”
lZ G, + Ci= + GBO+ G,,i,.
6.0
3
NCXldiabetic
Diabetic
Flat
7.4
13.0
6
9.0
1.2
+ 2.27
8.0
9.4 f
12.8
Non *abetic
6
59
1
Fasting
Diabetic
120 min
Diabetic
Nondiabetic
60 min
Diabetic
47
With Peek
30 min
NUVlbW
Examined
Insulin Curve
5.8
28.0
29.8
34.6
35.5
17
0
k 3
+ 11.2
t
A 1.5
12.6
+ 1.5
+ 12.7
f
f 3.6
t 2.2
8.5
1 .o i- 2.0
0.4
48.0
54.5
4.7
8.6
8.0
120 ml”
of comparisons)
r 10.4
t 3.3
10
21 i. 2.7t
60 min
From Fasting Level
p x 4-number
+ 1.7
* 3
+ 7.0
f 5.2
+ 5.4
+ 2.6
p < 0.05.
p (“exact”
3.0
5.8
14.0
13.2
23.0
25.0
12.5
34 + 3.2f
30 min
lncnsse
Underweight
Table 3. Plasma Insulin Levels (Mean au/ml
<: 0.05.
1179
413
744
444
781
445
423
2 225t
* 23
* 53t
f 9
f 40’.
* 9.1
803
_+ 10.5$
min
GlUCOSEl*
O-120
Number
6.0 19.0
2
10.2
11.3
1.9
1.0
1.3
3
f 2.2t
+_ 2.0
f 2.8
f
12 *
11 t
152
12 f 2.5
Fasting
3
5
23
9
55
2
30
Examined
f 8.6
f 6.2$
5.0
+ 1.2
1.0 f 2.0
33.4
31.9
28 -t 4.0
38 2 3.7
93 f 21t
* 13.7
t 7.4
10
7.0
+ 0.4
1.3 -r 3.0
57.4
40.2
60 t
53 f 5.7$
67 i Ott
28 k 6.4
60 min
+ 3.0$
t 48$
zt 6.8
t f
12
11.4
6.0
t 2.3
1.7 ). 2.9
71.2
64.8
36 f: 5.7t
20.7
102.0
22.4
120 min
lncressa From Fasting Level
55 * S.lt.
30 min
Overweight
‘_ SE1 in Diabetics and Nondiabetics Following Oral Glucose Load
Glucose+
886
334
784
459
783
* 52t
+ 42
+ 40t
r 15
zt 44t
2 10
* 94t
885
484
+ 15
448
O-120min
COHEN ET AL.
720
maximum insulin response at 30 min, whereas in the diabetic subjects only 8.3% of the cases had a peak at 30 min. At 60 min, 48.4% of the nondiabetics and 50% of the diabetics had a peak. Of the diabetic subjects, 16.7% had a flat curve, versus 7.4% in the nondiabetic subjects. In the overweight category, 28% of the nondiabetic subjects and 8.3% of the diabetics had a maximum response curve at 30 min whereas 48% of the nondiabetics and 50% of the diabetics had a delayed response with peak at 60 min. There is no significant difference in the extent of insulin response of the nondiabetic and the diabetic in the corresponding types of curves (as multiple comparisons were made, the “exact” p was multiplied by 4, which is the number of comparisons in each instance) except for the 30-min peak curve of the underweight group (Table 3) and the 60-min values of the 30-min peak of the overweight group as well as the
different age groups vary inconsistently with age. In the several cases where the insulin values are lower in the older age group, the difference is not significant. In a large proportion of the overweight group, especially in males, the insulin values following the glucose load are significantly higher when compared to the corresponding underweight groups. Table 6 shows the ratio of the increase of blood glucose level from fasting levels to the corresponding increase of insulin values from fasting levels at 30, 60, and 120 min after the glucose load in the different types of insulin response curves. It is evident that the higher glucose insulin ratio in the diabetics at the different periods and in all types of insulin response curves are attributable to undue hyperglycemia, since insulin increments at these times were not different from those present in the normal glucose tolerance. The correlation index of plasma triglyceride. plasma cholesterol, and LDL- and HDL-cholesterol levels as related to age and sex in nondiabetic subjects is shown in Fig. 4. In both males and females the regression analysis (r) for the increase of total cholesterol and of LDL-cholesterol levels, with age, was signi~~nt, whereas for the TG level it was not significant. The regression analysis for the increase of‘ HDLcholesterol level, with age, was signihcant for females, but not for males. Mean plasma triglyceride, plasma cholesterol, LDLand HDL-cholesterol levels and HDL/LDL ratio are shown in Table 7. The mean plasma triglyceride was higher in overweight males and females as compared to underweight, but significant only in overweight nondiabeti~ males. Plasma cholesterol levels were in general higher in overweight as
120-min values of the 618min peak of the overweight group. The fasting insulin in the diabetics was not significantly different from that of the nondiabetics in the underweight group. In the overweight group, the fasting insulin of the diabetics was higher in the flat curves. Table 4 details the absolute blood glucose levels following OGTT in the underweight and overweight nondiabetic subjects in the different age groups. No difference due to aging was noted in the blood glucose values at 60 and 120 min following glucose load. It appears that females have lower blood glucose values than males, but the difference is not statistically significant. Table 5 details the insulin response following OGTT in the nondiabetic underweight and overweight subjects of the different age groups. It is apparent that the plasma insulin levels in the
Table 4. Glucose Tolerance Test in Nondiabetics of the Different Age Groups (Mean mg/lOO ml t SE) Overweight
Underweight
Ttme Followng
Tsme Following Glucose Load Exammed
0 in,”
Glucose Load
Numbw
Number Age Group
60 mm
120 min
Examined
0 min
60 mu?
120 ml”
30-44 MElie
32
86 + 1.5
110 i 2.9
86 t 2.4
22
86 I
1.8
118 t 3.7
94
Female
21
81 i- 2.0
110
t 3.2
90 f 3.5
27
86 ? 2.2
115 t 4.1
34 ? 3.1
+ 3.3
45-55 MaI@
15
87 t 2.3
125 t 4.4
65 f 3.8
18
86k22
131 12.2
92
f 3.6
FCllWle
12
87
116
c 6.7
86 + 5.3
19
83 ? 2.7
118
+ 4.5
95
r 3.5
Male
32
67 i 2.3
121 _i 2.9
82 + 3.1
20
so i 3.4
122
+ 4.9
95 f 4.3
Fi?m&e
10
64
117
87 f 5.0
9
85 t 2.5
I12
+ 6.6
96
i
1.9
55t
r 4.0
t 3.9
r42
Number
32
10
55+
15.0
11.9
t 3.6
i; 1.7
i 2.3
t 0.7’
t 1.2
t 1.2
39.0
23.0
30.0
29.0
27.2
+ 4.8
+ 3.4
+ 4.2
* 3.2
lr 6.0
i: 4.4
30 min
35.7
overweight, “corrected” p < 0.05.
12
*Underweight
21
30-44
45-55
Females
12.6
9.4
15
55+
9.8
32
12.6
Fasting
45-55
vs.
Examined
30-44
M&5
Ase GWJP
(Mean flu/ml
37.8
28.2
25.6
34.2
26.0
25.9
i 8.0
f 7.4
+ 3.0
k 4.2
-c 6.2
2 4.3
60 min
-
4.8
17.5
9.8
11.1
8.5
12.7
1.9
x 5.1
* 6.6
i
+ 2.0
+ 5.0
t 2.2
120 ml”
;t SE) in Nondiabetics
increase From Fasting Level
Underweight
Table 5. Plasma Insulin Response
9
19
27
20
18
22
Exammed
Number
in Different
11.4
9.9
10.7
15.9
17.0
12.9 1.4
1.3 + 1.7
f
i- 1.2
+ 5.8
+ 2.4t
i
Fasting
48.9
29.4
34.0
37.8
48.0
50.0
i
11.0
zt 8.0
r 4.8
i: 7.8
+ 7.2
+ 5.6
30 min
Overweight
32.3
25.0
34.8
38.0
56.2
46.4
* 8.0
2 5.2
t 4.4
+ 5.6
zt 8.0’
f. 4.9*
60 min
Increase From Fasting Level
Age Groups Following Oral Glucose Load
35.3
14.5
26.7
25.0
24.6
33.3
f 9.0.
A 3.9
f 3.9’
+ 10.0
e 6.3
* 6.7’
120 min
COHEN ET AL.
722
Table 6. Glucose/Insulin Time Following Glucose
Insulin response-peak
+ SE) in Nondiabetic,
Borderline,
and Diabetic Glucose Tolerance
Underweight
Load
(mini
Ratios (Mean
NondiabetIc at
Tests
Overweight
Borderline
Diabetic
Baderline
NondiabetIc
Diabetic
30 min
30
1.52
+ 0.17
3.94
5.06
1.14
t
1.40
18.9
t
10.8
60
1.52
+ 0.20
3.7
8.50
1.50
t: 0.47
30.4
i
12
? 0.94
3.8
9.33
0.20
+ 0.30
27.0
f; 6
120
-0.60
I?
48
insulin response-peak 30 60 120
+ 0.34
8.50
+z 3.9
24.5
r 2.12
2.76
-f 0.54
2.40
+ 0.6
5.7
i
4.60
r 2.8
8.5
f 0.92
1.04
* 0.22
1.40
t 0.3
2.9
f 0.6
+ 1.00
4.00
r
1.0
t 0.62
1.44
+ 0.72
3.5
59 at
1.6
6
+ 7.7
-0.7
6
55
9
r
1.1 1.0
12
120 min 4.87
60
PO.8
120
2
+ 0.23
30
”
32
1.54 -0.82
response-peak
1
2.25
n Insulin
1
at 60 min
-0.24 6
* 2.98
2.50
i: 0.80
47.0
+ 17.0
4.03
z+ 1.66
3.65
+ 0.73
4.80
t 8.74
+ 2.7
4.50
+ 2.6
11.6
c 4.8
1.48
i 0.44
3.30
+ 0.80
4.15
+ 0.82
zt 0.3
2.00
+ 1.2
3.08
+ 0.7 1
0.80
+ 0.1
0.88
3
3
compared to underweight subjects, but these differences were not statistically significant. Mean LDL-cholesterol was variable among the groups, and significantly higher in overweight diabetic males. Plasma HDL-cholesterol levels were in general lower in overweight subjects, but significant changes were noted only in nondiabetic males. Significant increases of mean blood lipid levels from nondiabetic through borderline and
23
_t 0.16 10
._
t 0.8 2
diabetic subjects were noted in the following measurements and categories: with plasma TG (underweight diabetic males and overweight diabetic females), plasma cholesterol (underweight diabetic males and overweight diabetic males), and plasma LDL-cholesterol (overweight diabetic males). The HDL/LDL cholesterol ratio was lower in overweight than in underweight subjects, significantly so only in the case of diabetics.
FEMALES
AGE ormfs~
3.1
n-c
yemenltes.
11
Diabetic
18.0
tp -c0.05,
-C 0.05,
13
Diabetic
lp
177
13
212
207
186
211
188
179
12.9.
+ 11.6’
+ 14.6
+ 4.4
t
k 16.0
+ 2.9
Plasma
3 5.0 18.0 7.3*t
t
140 133 I
1.3t
36 k 3.6
39 + 2.7
39 f
49 + 7.0
112 it 6.3
114
0.353
41 + 6.5
+ 0.038
t 0.02 + 0.06 + 0.005’t
0.372
0.289
r 0.050
+ 0.057
0.327
0.370
0.462
47 ? 1.9
126 rt. 13.7
HDL
113 * 3.5
LDL
HDL/LDL
Lipid Levels of Nondiabetic,
Cholesterol (mg/dl)
overweight vs. underweight of the respective group.
diabetic vs. nondiabetic within the PI group.
+ 36
f 31.0
136 f 8.0t
164
51
Nondiatwtic
128 + 9.5.
115 *
96 zt 5.3
(m&II
TG
Plasma
Borderline
Overweight
9
72
Examined
Bwderline
Nondiabetwz
Undwweight
Subiects
Number
Male
Table 7. Plasma and Lipoprotein
11
11
46
1
4
43
Examined
Number
Borderline,
f 6.5
135
+ 14.0.
117 + 17.0
101
103
81 + 12.0
SO f 3.6
(mg/dl)
TG
PlaSma
and Diabetic
183
199
227
194
183
11.3
+ 7.5
r 10.3
A 5.0
199
f
f 4.1
12.2
f 5.3
133
f
134
+ 10.4
138 f 9.6
137
122
124 f 4.8
LDL
Cholesterol
t SE)
Female
(Mean
Plasma
Subjects
0.341 0.275
47 f 2.3 35 a 3.7
42 + 1.6
0.328
0.387 45
0.368 44 t 3.3
k 0.514.
k 0.003
-r 0.019
0.338
f 0.057
k 0.022
HM/LDL
43 f 2.4
HDL
hng/dl)
E
P
724
COHEN ET AL.
Table 8. Incidence of Hyperlipoproteinemia Diabetic,
(%I Among
Nondiabetic.
Borderline
and Diabetic Subjects
Subject
Examned
IIA
IIB
219
2.3 15)’
0.9 (21
LipoproteinType
Number
Nondiabetic
IV
7.7 (17)
Borderline
31
6.4 (2)
3.2 (1)
12.9 (4)
Diabetic
36
11.1 (41
2.8 (1)
13.9 (5)
67
9.0 (6)
3.0 (2)
13.4 (9) .-I__
esting to note that in diabetic subjects with hyperlipoproteinemia, the HDL/LDL cholesterol ratio was lower than in nondiabetics with comparable lipoprotein profiles. These differences are significant for type 1la and I lb. DISCUSSION
Diabetic IBorderline ‘Number
in parentheses represents number of subjects with
specified lipoprotein type. x2 nondiabettc vs. diabetic = 9.5472.
p c 0.05 (df -= 1).
x2 Nondlabetvz vs. borderline = 5.3424,
p. NS Idf = 1).
The incidence of hyperlipoproteinemia in nondiabetic, borderline, and diabetic subjects is shown in Table 8. it is evident that in diabetic subjects, all three types of hyperlipoproteinemia were more common than in nondiabetic subjects. We are aware of the small number of cases of diabetics, but we still calculated the x?: nondiabetic versus diabetic = 9.5472, p -: 0.05 (df = I ). Mean plasma lipid and lipoprotein levels of subjects with normal lipoprotein profile and the three types of hyperlipoproteinemia encountered in the study population are shown in Table 9. As expected, LDL-cholesterol levels were elevated in subjects with types Ila and Ilb and TG was elevated in types Ilb and IV when comparing hyperlipoproteinemic subjects to those with normal lipoprotein pattern, either in the nondiabetic, borderline, or diabetic subjects. It is inter-
Table 9. Plasma and Lipoprotein
of Diabetes
Our diagnostic
criteria for diabetes meliitus based on both a I-hr value of 190 mg/IOO ml and a 2-hr value of 140 mg/ 100 ml glucose following an oral glucose load satisfy the commonly used criteria.14.‘” This abnormal glucose tolerance test indicates “chemical and not necessarily “clinical diadiabetes” betes”.” The percent of maturity-onset diabetes in the examined population is 11.X% (I 3.3% in males and 9.7% in females). These results arc not different from those observed in other studies outside Israel.” ” The present results confirm our previous observations’ that on changing the environment, this population, in which almost no diabetes was detected 20 yr ago. now has a prevalence of diabetes comparable to other affluent communities. The incidence of maturity-onset diabetes increased with age and was higher in individuals who were overweight. In spite of the small number of cases, WC calculated the x’. which is significant for overweight females, but not for males. This is in accordance with the known fact
Lipid Level Among Subjects With Normal Lipoprotein Hyperlipoproteinemia
Llpoproteln Pattern
Prevalence
(Mean
Cholesterol
TG
Plasma
Profile and With
i SE1 lmgidl)
LOL
HDL
--_-HDL/LDL
NondiabetIc 88 t 2.7
175 f 2.0
114 t 1.9
IIA (5)
Normal (195)’
101 1? 11.1
274 i- 3.1
232 -t 10.0
IIB (2)
242 I 4.5
317 -t 16.5
243 f 11.5
IV (17)
273 + 15.6
205 i 6.7
102 + 7.1
44 1- 1.0 44.6
0.386
f 0.008
f 3.2
0.257
-r 0.027
36 * 0.5
0.176
? 0.1
0.340
f 0.023
0.362
i 0.035
35.2
+ 2.1
Borderline Normal 124) IIA 121 flB (1) IV (4) Diabetic
89 + 6.7 131 -r 27 203 461 + 129
177 i 7.0
116 ?r 5.7
42 5 3.6
289 + 11.5
221 * 4.0
41 +6
289 244 ?: 43
214
35
0.1829
i 0.03
0.1636
108 r 20
59 t- 13
0.458
Normal (26)
116 +8t
187 t 6.0
122 15.7
41 -c 3.3
0.3515
IIA (4)
122 * 34
301 + 23.7
226 + 12.6
35 t 0.5
0.182
IIB (1)
250
284
IV 151
310 ” 66.9
209 rt 18.2
*Number in parentheses represents number of subjects. tNondiabetic vs. diabetic p --c0.05.
219 131 k 8
29 36 i; 5.3
t 0.10 2 0.037 + 0.004t
0.132 0.2666
.k 0.028
DIABETES, BLOOD LIPIDS, AND ENVIRONMENT
that obesity significantly alters glucose tolerance.*’ It is noteworthy that in this population the effect of obesity on the prevalence of diabetes was more pronounced in females than in males. While the effect of overweight versus underweight on the increase in the prevalence of diabetes in males was observed in the older age group only, in females its expression was significant and evident in the younger age groups as well. It remains to be seen whether obesity is the primary cause for the increased prevalence of diabetes or if it accompanies diabetes as part of the metabolic changes that have occurred in this population on changing their environment, since in males there was a pronounced increase in the prevalence of diabetes in the underweight group as well. The prevalence of maturity-onset diabetes in males was higher than in females in the underweight group, whereas in the overweight group the prevalence in females almost equaled that of males. This higher diabetic male/female ratio was also observed in our previous survey among the old settled Yemenites’ and in other populations.“-24 The role of obesity in the change of this ratio observed in the present study may explain the changing sex incidence of diabetes that was observed in recent decades in the “developed countries” where an increase of diabetes among females was found in all age groups.‘~ “-*’ Several authors reported an initially delayed insulin response to hyperglycemia as a common feature to all forms of maturity-onset diabetes mellitus from prediabetes,28,29 the mildest forrns30 and the clinical overt disease.“-33 However, other investigators have reported identical or greater insulin response to intravenous or oral glucose in diabetic subjects, obese or nonobese, than in nondiabetics of comparable age, height, and weight.“, 34-36 We have therefore classified, both in the nondiabetics and diabetics, the insulin response curves according to the time of the maximal peak. It is apparent that in maturity-onset diabetics 91.7% of the underweight and 91.7% of the overweight have delayed insulin responses. It is noteworthy that among the nondiabetics, 53.4% of the underweight and 68% of the overweight also have delayed insulin responses with peaks at 60 or 120 min following the glucose load. However, the extent of the insulin responses of the diabetics, at all times, in the
725
corresponding types of insulin curves are not significantly different from the nondiabetics except for the cases with the 30-min maximal responses. The higher glucose/insulin ratio in the diabetics at the different periods of time, except for the flat curve responses, is attributable to undue hyperglycemia, since insulin increments at those times were not different from those present in the normal glucose tolerance. In conformity with other studies,37.3X our results indicate no significant difference in the fasting insulin levels between maturity-onset diabetics and nondiabetics in the underweight group. In the overweight group the fasting insulin level of diabetics with a flat curve are higher than the respective nondiabetic groups, as reported by Karam et al.39 Thus, in the early stages of adult-onset diabetes the fasting insulin and the insulin response is not different from that of the nondiabetic controls. It has been reported by some40.4’ that with advancing age there is deterioration of the mean glucose tolerance. However, our results are in accordance with other observers’B,4’,J’ who did not find any deterioration of glucose tolerance with age in nondiabetic individuals (i.e., those with normal glucose tolerance). Insulin release following glucose stimulation was also reported by some authors44,45 to deteriorate with age. Our results in the nondiabetics do not show any consistent pattern of change in the insulin response with advancing age, in conformity with the reports of other investigators 42.46 48 In the diabetic glucose tolerance curves, the ratio of glucose insulin increment from fasting level at 30, 60, and 120 min are higher than in the nondiabetic. This is attributable to undue hyperglycemia, since insulin increments at these times equaled those present in normal glucose tolerance, both in underweight and overweight subjects, except for the flat curves. It appears that in order to explain this fact one has to resort to “insulin resistance” or imply that the insulin molecule itself is structurally not intact. Obesity is frequently cited as a cause of insulin ineffectiveness, but this ineffectiveness was also evident in our nonobese diabetics. The maturity-onset diabetes mellitus, even in its early stages, is often defined as undue hyperglycemia resulting from a shortage of insulin. Our results cannot support this view. They
726
COHEN ET AL.
suggest rather that there is a shortage of insulin action. flood Lipids in ~o~diub~tic ~ubj~et~
Plasma cholesterol and LDL-cholesterol levels were significantly lower in the nondiabetic Yemenite settler described here compared to the non-Yemenites reported recently by Eisenberg’ and Klorfajn et a1.49(Table lo), whereas HDLcholesterol and plasma TG levels did not differ. However, the non-Yemenites were not screened for impairment of glucose tolerance and represented an urban population. The plasma cholesterol level in the non-diabetic Yemenite settlers now living in Israel for 25 yr is higher than levels found soon after their arrival in Israel, as reported by Toor et aL5’ and Brunner and Lobl.5’ In our nondiabetic population, the regression analysis did reveal a significant increase of total cholesterol and LDL-cholestero1 levels with age, whereas there was no such trend for an increase of plasma TG levels. This is in conformity with several authors52353who reported an increase of the blood cholesterol level with age in both males and females. Other investigators report no change with age.49.s4Obesity resulted in significant increases of plasma TG levels and decreased HDL-cholesterol levels in males but not females. Blood Lipids in diabetic Subjects
Plasma TG was increased in the diabetics, both male and female. The LDL-cholesterol was increased in males while no consistent trend was noted in the HDL-cholesterol levels. Higher prevalence of hyperli~mia among diabetic subjects as compared to nondiabetics was reported by several investigators.55--59Simi-
larly, in this unique Yemenite population in Israel, the incidence of hyperlipoproteinemia among the diabetics was more than twice that of nondia~ti~s, 27.7% and 1.096, respectively, whereas the per cent of subjects with different types of hyperlipoproteinemia was similar to that reported by other investigators.56-59These observations, together with those already discussed herein, indicate that in the Yemenite population an increase of plasma Iipid levels occurred during the 25 yr following immigration to Israel, most probably due to the changing environmental conditions. However, the expression of diabetes in this unique population, at least as related to the plasma lipid and lipoprotein levels, was similar to that of other non-Yemenite diabetic populations. The present study is the first investigation in Israel in which plasma HDL-cholesterol levels were determined in diabetic and nondiabetic subjects of one ethnic group living under similar environmental conditions. Clinical and epidemiologic studies show a consistent negative correlation between absolute plasma HDL concentration and coronary risk.60-62It has been postulated6’ that the “protective” effect of HDL may relate to the role of HDL in the removal of cholesterol from peripheral tissues.63.64Carew et alS6j suggest that raised HDL concentrations may limit the uptake by smooth muscle of the arterial wall of LDL, a lipoprotein that contributes to the initiation and progression of atherogenie lesions. The decisive factor in coronary risk is the relative HDL/LDL ratio at any given LDL concentration.b’.62 Our data (Table 7) suggests that in the underweight man and woman, HDLjLDL ratio is not affected by diabetes, while diabetes in the overweight male and female results in a decreased HDL/LDL ratio.
Table 10. Plasma Lipids and Cholesterol Levels in Yemenites and Non-Yemenites With Normal Lipoprotein Profile (Mean f SE) Cholesterol (mg/d~) Group
Nondiabetic Yemenites
NUmbar
Plasma TG
Examswd
fmgid4
219
105 + 2.7’
185 r 2.0
121 * 1.9
43 * 1.0
65
104 t 4.1
208 + 4.lt
139 + 2.q
44 + 2.1
386
112 + 2.6
227 * 2.1t
-
-
Plasma
LDL
HDL
Non-Yemenites (Eisenberg? Non-Yemenites (Klorfajn et al.“)
lt
= mean + SE.
tp < 0.01 Yemenites vs. non-Yemenites.
727
DIABETES, BLOOD LIPIDS, AND ENVIRONMENT
REFERENCES I. Cohen AM: Prevalence of diabetes among different ethnic Jewish groups in Israel. Metabolism 1050, 1961 2. Cohen AM, Eisenberg S: Ischemic heart disease in Israel. Cardiology Today 2 (3):7, 1974 3. New York Technicon Corporation: Autoanalyzer Methodology Manual N-24a. 1965 4. New York Technicon Corporation: Autoanalyzer Methodology Manual N-78. 1968 5. Burstein M, Samille J: Sur un dosage rapid du cholesterol lit aux a et aux @ lipoproteins du serum. Clin Chim Acta 5609, 1960 6. Lees RS, Hatch FT: Sharper separation of lipoprotein species by paper electrophoresis in albumin-containing buffer. J Lab Clin Med 61518, 1963 7. Hatch FT, Lees RS: Practical methods for plasma lipoprotein analysis. Adv Lipid Res 6:4, 1968 8. Friedenwald WT. Levy RI, Fredrickson DS: Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499, 1972 9. Eisenberg S: Typing of hyperlipoproteinemia in an Israel hospital. Isr J Med Sci 12: 126 I, 1976 IO. Beaumont JL, Carlson LA, Cooper CR, et al; Memoranda: Classification of hyperlipidemias and hyperlipoproteinaemias. Bull WHO 43:891, 1970 I I. Fredrickson DS, Levy RI: Familial hyperlipoproteinemia, in Stanburg JB, Wyngaarden JB, Fredrickson DS (eds): The Metabolic Basis of Inherited Disease (ed 3). New York, McGraw-Hill, 1972, p. 545 12. Society of Actuaries: Build and Blood Pressure Study, vol I. Chicago, The Society, 1959 13. Nie NH, Hull CH, Jenkins JG, et al: Statistical Package for the Social Sciences. McGraw-Hill New York, 1970 14. Fajans SS, Conn JW: Prediabetes, subclinical diabetes and latent diabetes: Interpretation, diagnosis and treatment, in Liebel BS and Wrenshaw GA (eds): On the Nature and Treatment of Diabetes. Amsterdam, Excerpta Medica Foundation, 1965, p 641 IS. Committee on Statistics of the American Diabetes Association: Standardization of the oral glucose tolerance test. Diabetes 18:299, 1969 16. Fajans SS: Tha natural history of idiopathic diabetes mellitus. Heterogeneity of insulin response in latent diabetes, in Creutzfeldt W, Kijbberling J, Neel JV (eds): The Genetics of Diabetes Mellitus. New York, Springer-Verlag, 1976. pp 64-78 17. Crombie DL: Incidence of glycosuria and diabetes. Proc R Sot Med 55:205,1962 18. Butterfield WJH: Summary of results of the Bedford diabetic survey. Proc R Sot Med 57:196, 1964 19. Genuth SM, Hauser HB, Carter JR Jr, et al: Community screening for diabetes by blood glucose measurement. Diabetes 25: I 110, 1976 20. West KM, Kalbfleisch JM: Glucose tolerance, nutrition and diabetes in Uruguay, Venezuela, Malaya and East Pakistan. Diabetes l5:9, 1966 21. Wilkerson HLC, Krall LP: Diabetes in a New England town: A study of 3516 persons in Oxford, Mass. JAMA 135:209,1947
22. Freedman LR, Blackard WC, Sagan LA, et al: The epidemiology of diabetes mellitus in Hiroshima and Nagasaki. Yale J Biol Med 37:283, 1965 23. Malins JM, Fitzgerald ME, Wall M: A change in the sex incidence of diabetes mellitus. Diabetologia I I2 I965
728
43. Dud1 J, Ensinck JW: Insulin and glucagon relationship during aging in man. Meta~lism 26:33, 1977 44. Crockford PM, Harbeck RJ, Williams RH: Influence of age on intravenous glucose tolerance and serum immunoreactive insulin. Lancet I :465, 1966 45. Barbagallo-Saugiorgi G, Ludicina E, Bompiani CD, et al: The pancreatic beta-cell response to intravenous administration of glucose in elderly subjects. J Am Geriatr Sot 18:529, 1970 46. O’Sullivan JB, Mahan CM, Freedlander AE, et al: Effect of age on carbohydrate metabolism. J Clin Endocrinol Metab 33:619, 1971 47. Streeten DHP, Gerstein MM. Marmor BM, et al: Reduced glucose tolerance in elderly human subjects. Diabetes 14:579, I965 48. Zentinogen IY, Cherondache CN, Pincus G: The process of aging: Serum glucose and immunoinsulin levels during oral glucose tolerance tests. J Am Geriatr Sot 17:i. 1969 49. Klorfajn I, Mizrahy 0. Assa S. et al: The blood level of lipid ingredients in the elderly. Harefuah 92106, 1977 50. Toor M, Katchalsky A, Agmon J, et al: Serum lipids and atherosclerosis among Yemenite immigrants in Israel. Lancet 1:1270, 1957 51. Brunner D, Lob1 K: Serum cholesterol, electrophoretie lipid pattern, diet and coronary artery disease: A study in coronary patients and in healthy men of different origin and occupation in Israel. Ann Intern Med 49:732, 1958 52. Lewis LA, Olmsted F, Page IH. et al: Serum lipid levels in normal persons. Findings of a cooperative study of lipoproteins and atherosclerosis. Circulation 16:227. 1957 53. Marmorston J, Griffith CC. Geller PJ, et al: Urinary steroids in the measurement of aging and of atherosclerosis. J Am Geriatr Sot 23:48 I, 1975
COHEN ET AL.
54. Hays D. Neil1 DW: Serum cholesterol and triglycerides in ischemic heart disease. Clin Sci Mol Med 26:185, 1964 55. Bergquist N: Serum lipids in ambulatory diabetic clientele. Acta Med Stand 187:213, 1970 56. Wilson DE, Schreibman PH. Arky R: Hyperlipidemia in an adult diabetic population. J Chronic Dis 23501, 1970 57. Leren P, Haabrekke 0: Blood lipids in normals. Acta MedScand 189:501, 1971 58. Wood PDS, Stern MP. Silvers A. et al: Prevalence of plasma lipoprotein abnormalities in a free-living ~pulation of the Central Valley. California. Circulation 45:114, 1972 59. Schonfeld G, Birge C. Miller JP, et al: Apolipoprotein-B levels and altered lipoprotein composition in diabetes. Diabetes 23:827. 1974 60. Berg K, B@resen AL: Serum-high-density-lipoprotein and atherosclerotic heart disease. Lancet 1:499, 1976 61. Miller GJ, Miller NE: Plasma-high-density-lipoprotein concentration and development of ischemic heart disease. Lancet I : 16, 197.5 62. Rhoads GG. Gulbrandsen CL, Kagan A: Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. N Engl J Med 294:293. 1976 63. Stein Y, Stein 0: High density lipoproteins reduce the uptake of low density lipoproteins by human endothelial ceils in culture. Biochem Biophys Acta 431:363, 1976 64. Miller NE, Weinstein DB, Steinberg D: Metabolism uf human lipoproteins, high density (HDL) and low density (LDL) of ~brobiasts of normal and of homozygous familial hyper~holesterolemic (FH) subjects. Clin Res 24:459 A, 1976 6s. Carew TE, Koschinsk T, Hayes SB, et al: A mechnnism by which high density lipoproteins may slow the atherogenic process. Lancet I : I3 15, 1976