Effects of Weight Loss on Mechanisms
of Hyperglycemia in Obese
Non-Insulin-Dependent Diabetes Mellitus
R. R. HENRY, P. WALLACE, AND J. M. OLEFSKY
SUMMARY
To quantitate the effects of weight loss on the mecha-
nisms responsible for hyperglycemia in non-insulin-de-
pendent diabetes mellitus (NIDDM), eight obese sub-
jects with NIDDM were studied before and after weight
reduction with posttreatment assessment after 3 wks of
isocaloric (weight maintenance) refeeding.
After weight loss of 16.8 ± 2.7 kg (mean ± SE), the
fasting plasma glucose level decreased 55% from 277
± 21 to 123 ± 8 mg/dl. The individual fasting glucose
levels were highly correlated with the elevated basal
rates of hepatic glucose output (HGO) (r = 0.91, P <
.001), which fell from 138 ± 11 to 87 ± 5 mg • n r 2 •
m i n 1 after weight loss. The change in fasting plasma
glucose also correlated significantly with the change in
the basal rates of HGO (r = 0.74, P < .05). This was
associated with reduced fasting serum levels of gluca-
gon (from 229 ± 15 to 141 ± 12 pg/ml), reduced free
fatty acids (from 791 ± 87 to 379 ± 35 |xeq/L), and un-
changed basal insulin levels (17 ± 4 to 15 ± 2 fill/ml).
Peripheral glucose disposal, assessed by the eugly-
cemic glucose-clamp technique, at insulin infusion
rates of 120 and 1200 mU rrr 2 • m i n 1 increased be-
tween 135 and 165%, from 128 ± 17 to 288 ± 24 mg
m~2 • m i n 1 during the 120-mU • rrr 2 • m i n 1 studies
and from 159 ± 19 to 318 ± 24 mg rrr 2 • m i n 1 dur-
ing the 1200-mU • rrr 2 • m i n 1 clamp studies, despite
comparable steady-state serum insulin levels at each
infusion rate before and after weight loss. HGO during
the 120-mU rrr 2 m i n 1 clamp studies increased from
85% to complete (100%) suppression after treatment.
Adipocyte size was reduced 44% (851 ± 91 to 475 ±
48 pi), whereas surface area decreased by 32% (4.30 x
104 to 2.92 x 104 (imVcell). Insulin binding to isolated
adipocytes was unchanged, whereas basal in vitro
From the Department of Medicine, University of California, San Diego, La Jolla,
CA; the San Diego Veterans Administration Medical Center, San Diego, CA;
and the Department of Medicine and Clinical Research Center, University of
Colorado Health Sciences Center, Denver, CO.
Address reprint requests to Robert R. Henry, M.D., Veterans Administration
Medical Center, Medical Research Service (V-111G), 3350 La Jolla Village
Drive, San Diego, CA 92161.
Received for publication 30 October 1985 and in revised form 10 March 1986.
990
rates of 3-O-methylglucose transport increased from
0.21 ± 0.13 to 0.53 ± 0.24 pmol/(2 x 109 »tm2) x (10
s~1) and maximal glucose transport rates increased
from 0.64 ± 0.29 to 1.18 ± 0.48 pmol/(2 x 105 cells) x
(10 s 1 ) and 0.42 ± 0.20 to 1.04 ± 0.30 pmol/(2 x 109
urn2) x (10 s- 1 ).
Finally, absolute serum insulin levels during oral glu-
cose-tolerance tests and meal-tolerance tests were un-
changed by weight reduction, whereas plasma glucose
levels were markedly reduced.
We conclude that in obese NIDDM, weight loss re-
sults in improved glucose homeostasis with 1) reduced
basal HGO predominently responsible for the lowering
of fasting glucose levels; 2) improved postprandial glu-
cose excursions with marked amelioration of peripheral
insulin resistance due to improved postreceptor insulin
action, which is at least partly due to enhanced glu-
cose transport system activity; and 3) unchanged ab-
solute insulin levels in the face of markedly reduced
glycemia, indicative of enhanced p-cell sensitivity to in-
sulinogenic stimuli. DIABETES 1986; 35:990-98.
M
any patients with non-insulin-dependent diabe-
tes mellitus (NIDDM) are obese, and numerous
studies have demonstrated improved glucose
tolerance after weight loss.1-10 However, the
mechanisms underlying the beneficial effects remain in-
completely understood because most studies have assessed
the influence of weight loss on only one specific abnormality.
Furthermore, the changes reported after weight loss have
often been contradictory. Thus, although the hyperglycemia
of NIDDM is the result of a combination of decreased insulin
secretion, elevated rates of hepatic glucose output, and pe-
ripheral insulin resistance,11 the relative contribution of
changes in each of these abnormalities to the improved gly-
cemia after weight loss is not known.
Weight reduction in obese nondiabetic subjects leads to
improved tolerance to oral glucose and increased peripheral
sensitivity to insulin.12-15 In obese subjects with NIDDM, a
recent report indicates that the elevated basal hepatic glu-
DIABETES, VOL. 35, SEPTEMBER 1986
cose output (HGO) is reduced after weight loss,8 whereas
the insulin secretory response to various stimuli is improved
in some studies13-61016"18 and unchanged in others.89 Even
the few studies that have measured peripheral insulin re-
sistance in NIDDM have been conflicting, with reports of both
improvement9 and no change8 after weight loss.
To help clarify these issues, we have measured insulin
secretion, HGO, and insulin resistance in a group of obese
NIDDM subjects before and after weight loss during a period
of weight-maintenance refeeding.
MATERIALS AND METHODS
Subjects. This study was conducted on eight obese subjects
with NIDDM19 who were otherwise healthy. After written, vol-
untary, informed consent, all subjects were admitted to the
clinical research ward and underwent a complete medical
history, physical examination, electrocardiogram, and chest
X-ray. The next day, after an overnight fast, a chemistry panel
and urinalysis were done. Subjects were screened to ensure
a stable body weight for at least 2 mo before admission.
During diet therapy, subjects were encouraged to maintain
their usual level of physical exercise. During initial weight
reduction, all subjects were hospitalized from 10 to 40 days
and then followed as outpatients. The duration of the weight-
reduction period ranged from 60 to 380 days. Seven subjects
had been on oral hypoglycemic agents, one was untreated,
and none had ever been on insulin therapy. Oral hypogly-
cemic agents were withdrawn at least 3 wk before entry into
the study. One subject was on maintenance thyroxine ther-
apy, and no medications were taken that were known to affect
carbohydrate metabolism. Additional characteristics of the
study subjects are shown in Table 1.
Diets. For at least 3 days before and then during each series
of studies, subjects consumed a weight-maintenance liquid-
formula diet (30 kcal/kg) containing 45% carbohydrate, 40%
fat, and 15% protein given in three feedings of 1 /5, 2/5, and
2/5 of the total daily calories at 0800, 1200, and 1700 h,
respectively. Between study periods, the subjects consumed
a very low-calorie diet (MediBase, Advanced Healthcare, Pa-
cific Grove, CA), ranging from 330 to 600 kcal/day given in
three servings. This diet is a powdered preparation recon-
TABLE 1
Clinical and metabolic characteristics
Age (yr)
Sex
Duration of diabetes, yr
Therapy of diabetes
Weight, kg
Body mass index (kg/m2)
Fasting plasma glucose (mg/dl)
Total glycosylated hemoglobin (%)
Fasting plasma cholesterol (mg/dl)
Fasting plasma triglyceride (mg/dl)
Fasting serum free fatty acids (|xeq/!_):}:
Fasting serum insulin (^ll/ml)
Fasting serum glucagon (pg/ml)
Adipocyte cell volume (pi)
Adipocyte cell surface area ( x 10" n,m2)
Values are expressed as means ± SE (except for age, expressed as mean ± SD).
*P < .01. fP < 001. $N = 5. §P < .05.
DIABETES, VOL. 35, SEPTEMBER 1986
stituted to a liquid with ~8 oz of water per serving. It contains
55% carbohydrate, mainly from lactose and fructose, 42%
protein, primarily of milk and soy origin, and 3% milk fat, with
the essential fatty acids linoleic acid and linolenic acid, and
micronutrients to meet the daily requirements advised by the
National Research Council. After weight loss and for at least
3 wk before restudy, subjects were placed on a solid weight-
maintenance diet (30 kcal/kg) of the same composition as
the previously detailed liquid-formula diet.
Studies of insulin secretion. On separate days after a 12-
h overnight fast and at least 30 min after the placement of
an indwelling venous cathether, an oral glucose-tolerance
test and a meal-tolerance test were performed. For the oral
glucose-tolerance test, the subjects were given a 75-g load
at 8 AM consumed over a 15-min period, and blood samples
were obtained at 0,30,60,120, and 180 min for measurement
of glucose and insulin levels. During the meal-tolerance tests,
blood samples were obtained in the fasting state and at
hourly intervals throughout the day for measurements of glu-
cose and insulin levels while the subject ingested, over a 30-
min period, the allotted morning and noon portions of the
liquid-formula diet described above. The morning portion
(1/5 of total calories) was ingested immediately after the
fasting sample was obtained and the noon meal (2/5 of total
calories) was taken immediately after the 4-h sample was
drawn. These studies were conducted before and then after
weight loss.
Euglycemic glucose-clamp studies. In vivo insulin sensi-
tivity was measured by a modification of the euglycemic glu-
cose-clamp technique as previously described.20 At 0700 h
after a 12-h overnight fast, an intravenous catheter was
placed in an antecubital vein for infusion of insulin, glucose,
[3-3H]glucose (New England Nuclear, Boston, MA), and po-
tassium phosphate. Another catheter was placed in a ret-
rograde manner into a dorsal hand vein and kept in a warming
device at 70°C. After insertion of the catheters, [3-3H]glucose
was infused for at least 120 min before initiating the insulin
infusion. A priming dose of insulin was administered during
the initial 10 min in a logrithmically decreasing manner to
acutely raise serum insulin to the desired level, where it was
maintained for the duration of the study by a continuous
Before treatment After treatment
54 ± 4
5 male, 3 female
7± 2
7 on hypoglycemic agents,
1 on no treatment
102.9 ± 5.1 86.1 ± 3.7*
34.4 ± 1.8 28.7 ± 1.0*
277 ± 21 123 ± 8 t
11.9 ± 0 . 8 7.5 ± 0.4*
181 ± 14 135 ± 12*
351 ± 124 125 ± 22*
791 ± 87 379 ± 35§
17±4 15 ± 2
229 ± 15 141 ±12t
851 ± 91 475 ± 48f
4.30 ± 0.31 2.92 ± 0.20f
991
insulin infusion. The amount of insulin given during the initial
10-min period was roughly twice that given during each sub-
sequent 10-min interval by continuous infusion. Plasma glu-
cose was maintained between 80 and 90 mg/dl throughout
the study period, with a coefficient of variation of <5%, by
means of a variable rate of infusion of 20% dextrose. After
initiation of insulin infusion, the serum glucose level was al-
lowed to fall to - 1 0 0 mg/dl before initiating the infusion of
20% glucose. Based on plasma glucose measurements done
at 5-min intervals, the glucose infusion was adjusted as
needed to maintain the plasma glucose level at —85 mg/dl
during the period the measurements were made. Potassium
phosphate was administered at a rate of 15-20 meq/h to
maintain the serum potassium level between 3.5 and 4.5
meq/L and thus avoid hypokalemia or hypophosphatemia.
Each subject was studied at an infusion rate of 120 mil •
rrr 2 • min~1 to allow assessment of both submaximal pe-
ripheral glucose disposal and suppressibility of HGO. In ad-
dition, on a different day each subject was studied at an
insulin rate of 1200 mU • m~2 • min~1 to assess maximum
stimulation of overall glucose disposal. Because suppression
of HGO might not be complete in diabetic subjects during
the insulin infusion rate of 120 mU • rrr 2 • min~\ the overall
glucose disposal rate was determined isotopically (see next
section) for each 20-min interval after achieving euglycemia.
Endogenous glucose production is completely suppressed
during the 1200-mU • m~2 • min~1 insulin infusion so that the
total glucose disposal rate is equal to the exogenous glucose
infusion rate. Due to variability in the length of time required
to attain steady-state insulin effects on glucose kinetics, all
studies were carried out for at least 180 min or for 60 min
after stable glucose infusion rates at euglycemia. The data
for the last three 20-min intervals of each study were sub-
sequently meaned and used as the data point for that par-
ticular study. Glucose-clamp studies were carried out for the
identical duration of time before and after weight loss, with
comparison of the same 20-min data points. Urinary glucose
loss was not measured with all studies conducted under
euglycemic conditions. All subjects were restudied in an
identical manner after weight loss.
Hepatic glucose output. The rate of glucose appearance
(Ra) and the rate of overall glucose disappearance (Rd) were
quantitated in both the basal (postabsorptive) state and dur-
ing the 120-mU • rrr 2 • min" 1 glucose-clamp studies by in-
fusion of [3-3H]glucose in a primed continuous manner.2021
With this technique, 30 ixCi of the tracer was injected as a
bolus, followed by a continuous infusion rate of 0.60 ixCi/
min. Blood samples were obtained at 20-min intervals for the
determination of both the concentration and sp act of glu-
cose. Ra and Rd were then calculated from the Steele
equations22 in their modified derivative form21 because the
tracer exhibits non-steady-state kinetics under these condi-
tions. The rate of HGO was then calculated, knowing that Ra
represents the sum of HGO and the rate of infusion of ex-
ogenous glucose. Measurements of HGO were made before
diet therapy and again after 3 wk of weight-maintenance
refeeding.
Adipocyte insulin binding and 3-O-methylglucose trans-
port. Isolated adipocytes for insulin binding and 3-O-meth-
ylglucose transport were prepared from tissue obtained from
open biopsy of the lower abdominal wall. The biopsy was
992
performed on the day before the initial glucose clamp in all
subjects both before and after weight loss. The methods of
these procedures have been described in detail previously.23
Analytic methods. Blood for glucose determinations was
drawn, and the plasma was immediately separated with a
Beckman microfuge (Beckman, Palo Alto, CA) and measured
by the glucose oxidase method with a Beckman glucose
analyzer (Beckman, Fullerton, CA). Blood for the determi-
nation of serum insulin and free fatty acids was collected in
untreated tubes and allowed to clot at room temperature.
Blood for glucagon determination was collected in tubes con-
taining a protease inhibitor (Trasylol, 500 KlU/ml; F.B.A. Phar-
maceuticals, New York, NY) and allowed to clot at room tem-
perature. Blood for glucose sp act was collected in tubes
containing potassium oxalate and sodium fluoride and im-
mediately placed on ice until spun. These specimens were
then centrifuged, and the serum was removed and stored at
-20°C until the determinations were made. Blood for total
cholesterol and triglycerides was collected in EDTA-treated
tubes, centrifuged, and refrigerated at 4°C until assayed.
Serum insulin levels were measured by a specific double-
antibody radioimmunoassay according to the method of Des-
buquois and Aurbach.24 Serum glucagon was assayed by
the charcoal-separation method of Unger and Faloona.25 Free
fatty acids were determined in serum by an enzymatic col-
orimetric method kit (Wako Pure Chemical Industries, Osaka,
Japan). Total cholesterol and triglyceride were measured en-
zymatically.2627 Total glycosylated hemoglobin was deter-
mined in heparinized blood by the Fast Hemoglobin Test
System kit (Isolab, Akron, OH).
Data analysis. All calculations and statistical analyses were
performed on a Digital P.D.P. 11/24 computer (Digital, May-
nard, MA) with the CLINFO data-base management and anal-
ysis program (Bolt, Beranek, and Newman, Cambridge, MA).
For statistical comparisons, analysis of variance (ANOVA) for
repeated measures and the Student's t test for paired data
were used. The Wilcoxon signed-rank test was used for anal-
ysis when the data was not normally distributed. Correlation
coefficients were calculated by the method of least squares.
Data are expressed as means ± SE unless otherwise stated.
RESULTS
The mean values of several metabolic variables measured
before and after weight loss and refeeding are listed in Table
1. The mean weight of the group fell from 102.9 ± 5.1 to 86.1
± 3.7 kg (P < .001), resulting in a total weight loss of 16.8
± 2.7 kg (range, 3.2-26.4 kg) or 16.4% of the initial mean
body weight. Similarly the mean body-mass index, which
correlates well with the degree of obesity, fell from 34.4 ±
1.8 to 28.7 ± 1.0 kg/m 2 (normal values: <25 for males, <27
for females19). The mean fasting plasma glucose level de-
creased from 277 ± 21 to 123 ± 8 mg/dl (P < .001), and
the total glycosylated hemoglobin fell from 11.9 ± 0.8 to 7.5
± 0.4% (P < .001). Significant reductions also occurred in
the fasting levels of plasma cholesterol, from 181 ± 14 to
135 ± 12 mg/dl (P < .01); plasma triglyceride, from 351 ±
124 to 125 ± 22 mg/dl (P < .01); and serum free fatty acids,
from 791 ± 87 to 379 ± 35 ixeq/L (P < .05). The mean
fasting serum insulin concentration was not significantly dif-
ferent at 17 ± 4 and 15 ± 2 |i,U/ml (P, not significant),
DIABETES, VOL. 35, SEPTEMBER 1986
 A

400 - * * * p<0.001
T T 150 • Before Diet
* /~ O After Diet

300 /
o

uli
o
o -
a 200
E ^ ^

s^ * •
Y 50
100

FIG. 1. Plasma glucose response (A) and serum

1 1 1 1 insulin response (B) to 75-g oral glucose-toler-
ance test before ( • ) and after (O) diet therapy.
30 60 120 180 30 60 120 180 Results are plotted as means ± SE. Shaded area
Time (minutes) Time (minutes) indicates normal range (means ± SE).

whereas the fasting serum glucagon level fell from 229 ± 15
to 141 ± 12 pg/ml (P < .001). There was a highly significant
reduction in both adipocyte cell volume, from 851 ± 91 to
475 ± 48 pi (P < .001), and surface area, from 4.30 ± 0.31
x 104 |xm2 to 2.92 ± 0.20 x 104 |xm2 (P < .001), after weight
loss.
Plasma glucose and insulin levels. The plasma glucose
and serum insulin responses after oral glucose and test meals
of mixed composition are shown before and after diet therapy
in Figs. 1 and 2, respectively. After weight loss, the mean
plasma glucose levels after the 75-g oral glucose load were
significantly reduced (P < .001) at all times measured (Fig.
1/4). In contrast, the corresponding serum insulin levels (Fig.
16) were not significantly different at any time interval [P(F1i7
= 1.11), not significant, ANOVA]. The glucose levels after
the morning and noon mixed meals are shown in Fig. 2k.
Again, the mean plasma glucose levels were significantly
reduced (P < .001) at all times, while the corresponding
insulin levels (Fig. 28) remained unchanged [P(F15 = 1.67),
not significant, ANOVA].
As shown in Fig. 3/4, the total area under the glucose curve
after the oral glucose challenge was reduced 44% from
62,151 ± 4362 before diet therapy to 34,519 ± 2936 mg •
dh 1 • min^1 after weight loss (P < .001). The total area under
the glucose curve during the meal-tolerance test was also
significantly reduced after weight loss, falling 58% from
160,196 ± 12,706 to 67,425 ±4534 mg • dh 1 • min~1 (P <
.001). The incremental areas under the glucose curve were
not significantly different after the oral glucose-tolerance tests
(from 13,596 ± 1006 to 10,534 ± 1425 mg • dl" 1 • mirr 1 , P,
not significant) but were significantly reduced (from 41,760
± 3420 to 18,480 ± 3060 mg • dh 1 • m i n \ P < .001) during
the meal-tolerance tests. The total areas under the insulin
curve (Fig. 36) were not significantly different before and

* p < 0.001
400
• Before Diet
150 o After Diet

D) 300

•= 100

200

50
100

FIG. 2. Plasma glucose response {A) and serum

insulin response (B) to test meals of mixed com-
position before ( • ) and after (O) diet therapy. Re-
8 9 10 11 Noon 1 2 3 10 11 Noon 1 3 sults are plotted as means ± SE. Shaded area in-
AM PM AM PM dicates normal range (means ± SE).

DIABETES, VOL. 35, SEPTEMBER 1986 993

 OGTT
16
*p < 0.001
FIG. 3. Total (D) and incremental ( 0 ) glucose re-
sponse (A) and total (D) and incremental ( 0 ) in-
sulin response (B) expressed as area under curve
during oral glucose-tolerance tests (OGTT) and
meal-tolerance tests (MTT) before and after diet
therapy. Results are plotted as means ± SE. Before After
Diet
after diet therapy after either the oral glucose-tolerance tests
(4374 ± 881 vs. 5571 ± 531 |xU • ml" 1 • mirr 1 , P, not sig-
nificant) or the meal-tolerance tests (17,276 ± 3726 vs.
19,091 ±2649(xU • ml" 1 • mirr 1 , P, not significant). Similarly,
the incremental areas under the insulin curves were un-
changed during the oral glucose-tolerance tests (1584 ± 349
vs. 2893 ± 440 |xU • ml" 1 • min~1, P, not significant) and the
meal-tolerance tests (9480 ± 2580 vs. 13,080 ± 1740
(xU • ml" 1 • rnirn1, P, not significant). The areas under the
glucose and insulin curves were greater during the meal-
tolerance tests than during the oral glucose-tolerance tests
due to the different duration of study times (7 vs. 3 h, re-
spectively).
Glucose-clamp studies. The individual and mean steady-
state rates of total glucose disposal and the corresponding
mean serum insulin levels attained during insulin infusions of
120 and 1200 mil • nrr2 • min~1 are shown before and after
weight loss in Fig. 4, A and B, respectively. After weight loss,
the glucose disposal rate increased an average of 165%,
from 128 ± 17 to 288 ± 24 mg -irr 2 • min" 1 (P < .001),
during the 120-mU • nrr2 • min 1 studies and 136%, from 159
± 19 to 318 ± 24 mg • m" 2 • min- 1 (P < .001), during the
1200-mU • rrr 2 • min" 1 clamp studies. The percent of maximal
effect on total glucose disposal achieved during the 120-mU
• m~2 • min" 1 studies remained essentially unchanged: 83%
before diet therapy and 87% after weight loss (P, not signif-
icant). The serum insulin levels at each infusion rate were
similar before and after weight loss at 353 ± 30 and 302 ±
27 |xU/ml, respectively (P, not significant), during the 120-
mU • rrr 2 • min" 1 studies and 8,699 ± 754 and 9,611 ± 437
(xU/ml, respectively (P, not significant), during the 1200-mU
• nrr2 • min" 1 study.
Basal hepatic glucose production rates. As shown in Fig.
5, the mean basal rate of HGO before diet therapy was 138
± 1 1 mg • m~2 • min~1 and fell to 87 ± 5 mg • irr 2 • min" 1
(P < .001) after weight loss, which is comparable to that
determined in nondiabetic control subjects (79 ± 3 mg • irr 2
• min"1). (One subject did not have basal HGO determined
during the study.) The mean basal plasma glucose level at
these rates of HGO was 263 ± 21 mg/dl before diet therapy
and 118 ± 6 mg/dl after weight loss (P < .001). The percent
994
MTT OGTT MTT
T 20
15
10
Before After Before After Before After
Diet Diet Diet
suppression of basal HGO was calculated from the values
obtained for residual HGO during the 120-mU • m~2 • min- 1
insulin infusion euglycemic clamp. The mean basal HGO was
21 ± 6 mg • irr 2 • min" 1 , or 85% suppressed, before diet
therapy and fell to - 4 4 ± 21 mg • rrr 2 • min" 1 after weight
loss. For the purpose of this study, these negative values
were assumed to indicate complete (100%) suppression of
HGO. When the basal HGO and the corresponding basal
plasma glucose levels of individual subjects were compared
both before and after weight loss, a very strong correlation
was present (r = 0.91, P < .001). A significant correlation
was also present between the change in basal HGO and the
change in the basal plasma glucose level (r = 0.74, P <
.05) after weight loss.
Insulin-binding studies. Figure 6 shows the competition
curves for insulin binding to adipocyte receptors before and
after weight loss. When expressed on the basis of cell number
(Fig. 6A), it is apparent that these curves are essentially
identical, implying that insulin binding to receptors is unaf-
fected by weight loss. However, after weight loss it may be
more appropriate to express the data per unit of cell surface
area, because adipocyte volume was reduced 44% (from
851 ± 91 to 475 ± 48 pi) after weight loss, whereas surface
area decreased by 32% (from 4.30 x 104 to 2.92 x 104|Arrr7
cell). When the insulin-binding data were normalized to cell
surface area (Fig. 66), the binding curves were still com-
parable with a significant increase in bindng (P < .05) noted
only at an insulin concentration of 5 ng/ml.
Adipocyte glucose transport. Basal and maximal rates of
3-O-methylglucose transport in isolated adipocytes are
shown in Fig. 7. When glucose transport is expressed per
cell number (Fig. 7A), the basal rate does not increase sig-
nificantly after weight loss [from 0.33 ± 0.20 to 0.62 ± 0.28
pmol/(2 x 105 cells) x 10 s" 1 (P, not significant)], whereas
the maximal rate does [from 0.64 ± 0.29 to 1.18 ± 0.48 pmol/
(2 x 105 cells) x 10 s~1 ( P < .05)]. When glucose transport
is expressed per unit surface area (Fig. 78), both basal [from
0.21 ± 0.13 to 0.53 ± 0.24 pmol/(2 x 109 |xm2) x 10 S"1
(P < .005)] and maximal [from 0.42 ± 0.20 to 1.04 ± 0.30
pmol/(2 x 109 n,m2) x 10 S"1 (P < .005)] rates of glucose
transport increased significantly.
DIABETES, VOL. 35, SEPTEMBER 1986
 R R HENRY P WALLACE. AND

nrr2 • min~1) as compared with nondiabetic controls (79 ±

3 mg • m~2 • min 1 ) and that a close relationship exists be-
tween basal HGO and the fasting plasma glucose level in
400 - individual subjects both before and after weight loss (r =
0.91, P < .001). Weight loss led to a 40% reduction in the
basal rate of HGO [from 138 ± 11 to 87 ± 5 mg • rrr 2 • min~1
en (P < .001)] with significantly increased sensitivity to insulin's
~ 300 h
0) suppressive effects during the euglycemic clamp studies
[from 85 to 100% suppression (P < .001)]. Furthermore, the
change in HGO was well correlated to the change in fasting
glucose level, indicating that the effect of weight reduction
to lower fasting glycemia was due to the fall in basal HGO.
We have previously shown that resistance to the in vivo
action of insulin to promote glucose disposal in NIDDM is
due to a combination of receptor and postreceptor defects.20
Before initiating dietary therapy, the peripheral uptake of glu-
cose determined by the euglycemic clamp technique at
steady-state serum insulin concentrations of 300 and 10,000
ixU/ml was markedly reduced compared with normal control
subjects (see Fig. 4). After weight loss and 3 wk of weight
stabilization, the mean in vivo glucose disposal rates ap-
12,000

10,000 A
* p < 0.001
T 300
8,000
3. ^ \
200 -
*==

100 -
400
T
T
T

200

150 ~
Before After Normal Before After Normal
Diet Range Diet Range

FIG. 4. Individual and mean glucose disposal rates {A) and corre-
sponding means ± SE of serum insulin levels (B) during 120-mU - m 2
• min' 1 insulin infusion rates (D) and 1200-mU m" 2 min 1 insulin 2 100 -
infusion rates (E3) before and after diet therapy. Glucose disposal rates
(means ± SE) in nondiabetic subjects are included for comparison,

(D
DISCUSSION
Despite numerous studies demonstrating the merits of weight
reduction in obese NIDDM,1-1016-18 little is known about the
mechanisms underlying this improvement. Our study docu-
ments that modest weight loss in obese NIDDM subjects
results in greatly improved carbohydrate metabolism asso-
ciated with improved insulin secretion, reduced basal HGO,
and enhanced in vivo and in vitro insulin action. These Before Diet After Diet
beneficial metabolic effects were not simply due to the
FIG. 5. Individual and mean fasting plasma glucose levels {A) and
hypocaloric state during weight loss because the post- hepatic glucose output (B) during the basal state (D) and during
weight-reduction studies were carried out after a weight- 120-mU • m 2 • min 1 insulin-infusion euglycemic clamp study (E) be-
maintenance refeeding period of 3 wk. fore and after diet therapy. Hepatic glucose output during euglycemic
clamp study is expressed as mean ± SE. Normal range (mean ± SE)
We demonstrated, as have others,28-32 that the basal HGO for basal hepatic glucose output in nondiabetic subjects is included for
is elevated in untreated diabetic subjects (138 ± 11 mg • comparison.

DIABETES, VOL. 35, SEPTEMBER 1986 995

5 1.0
Insulin Concentration (ng/ml)
proached those of normal subjects (increasing between 135
and 165%), clearly demonstrating the effects of weight re-
duction to ameliorate peripheral insulin resistance in NIDDM.
Earlier studies have shown improved insulin sensitivity after
weight loss in obese subjects with normal or impaired glu-
cose tolerance.12-15 However, the effects of weight loss on
insulin resistance in NIDDM have been more controversial.
Thus, Hughes et al.9 demonstrated improved insulin-me-
diated glucose uptake after weight loss in obese NIDDM. In
contrast, however, Bogardus et al.,8 using the euglycemic
clamp technique, documented significant improvement of
peripheral insulin resistance in obese NIDDM only when diet
therapy was combined with physical exercise, not with weight
loss from diet therapy alone. However, these workers studied
subjects with less severe diabetes (pretreatment fasting
plasma glucose 167 ± 28 mg/dl), who lost considerably less
weight (9.9 ± 1.3 kg) than those in our study (16.8 ± 2.7
kg)-
The mechanisms underlying this improvement in insulin's
effect to stimulate peripheral glucose disposal are partially
elucidated by our study. Thus, insulin binding to isolated
adipocytes was measured before and after weight reduction,
and little if any change was noted (see Fig. 6). The lack of
any effect of weight loss on insulin binding in our study is
discordant with previous reports of increased insulin recep-
tors on both monocytes33 and adipocytes3435 in obese sub-
r A
<2 1.5 1.5
E 1-0 .1.0
0.5 80.5
Before After Before After Before
Diet Diet
996
FIG. 6. Insulin binding to isolated adipocytes ex-
pressed as percentage 12sl-labeled insulin bound
per cell number {A) and per unit surface area (B)
before ( • ) and after (O) diet therapy. All data are
corrected for nonspecific binding and are plotted
as means ± SE.
jects after weight loss. Similarly, caloric restriction in obese
NIDDM subjects has been associated with increased insulin
receptors on circulating monocytes.510 The reasons for these
differences are not entirely clear but may indicate that obese
NIDDM subjects do not respond to weight loss as obese
nondiabetic subjects do or may reflect differences in cell type
responsiveness (note that monocytes are not a recognized
target tissue for insulin as are adipocytes). In addition, a
unique aspect of our study that might explain the discrepancy
in insulin binding is the prolonged period of weight-mainte-
nance refeeding (3 wk) after weight loss. Nevertheless, if one
assumes that insulin binding to adipocytes reflects insulin
binding to other target tissues (particularly skeletal muscle),
then it follows that the marked improvement in peripheral
glucose disposal must be due to enhanced postbinding
steps in insulin action. This concept is quite supportive of
earlier studies by ourselves20 and others36 demonstrating that
the major cause of the insulin resistance in NIDDM is due to
a postbinding defect in insulin action.
Thus, we have previously suggested that a defect in glu-
cose transport activity is an important contributor to the post-
binding defect in in vivo insulin action observed in NIDDM
subjects.37 Accordingly, in our studies we have measured
adipocyte glucose transport before and after weight loss and
have found substantial increases in glucose transport activ-
ity. In combination, these results demonstrating correspond-
* p < 0.05
FIG. 7. Basal and maximal rates (means ± SE) of
3-O-methylglucose transport in isolated adipo-
After Before After cytes expressed per cell number (A) and per unit
surface area (0) before and after diet therapy.
DIABETES, VOL. 35, SEPTEMBER 1986
ing increases in in vivo glucose disposal and in vitro adi-
pocyte glucose transport with no change in insulin binding
certainly support the concept of decreased glucose transport
as a major factor underlying insulin resistance before weight
reduction and of increased glucose transport activity playing
an important role in the amelioration of peripheral insulin re-
sistance induced by weight loss.
Plasma insulin levels after either oral glucose or mixed
meals did not change significantly after weight reduction.
Although it is possible that unchanged insulin levels could
result from counterbalancing changes in insulin secretion
and hepatic insulin extraction, this seems highly unlikely be-
cause the steady-state plasma insulin levels were compa-
rable during the euglycemic glucose-clamp studies (see Fig.
4) before and after weight loss. Therefore, it seems most
probable that the amount of insulin secreted to both oral
glucose and mixed meals was quite similar before and after
weight reduction. However, plasma insulin levels cannot be
properly interpreted without considering the prevailing levels
of glycemia. Glycemia was markedly reduced after weight
loss, and because the effects of hyperglycemia to potentiate
insulin secretion are well known,3839 the presence of un-
changed insulin levels in the face of reduced glucose levels
after weight loss are indicative of enhanced fJ-cell function.
In other words, weight loss apparently leads to improved
sensitivity of (S-cells to insulinogenic stimuli, allowing the pan-
creas to secrete similar amounts of insulin after weight loss
in the presence of much lower ambient glucose levels.
The total areas under the plasma glucose curves after oral
glucose or meals were greatly reduced after weight loss, and
this was predominantly due to the reduction in the fasting
plasma glucose level. The incremental glucose levels were
either unchanged (after oral glucose) or lower (after mixed
meals) after weight loss, and this indicates an improvement
in insulin-mediated postprandial glucose uptake. Thus, the
rate of glucose uptake is increased not only by insulin but
also by hyperglycemia. The higher the plasma glucose level,
the greater the mass-action effect of glucose to promote its
own uptake. Therefore, if insulin action is constant, the post-
prandial increments to a comparable incoming glucose load
will be lower the higher the ambient glucose level. At the time
of the post-weight-reduction studies, plasma glucose levels
were reduced by - 5 0 % indicating a twofold greater mass-
action effect of glucose to promote its own uptake before
compared with after weight loss. Despite this, the postpran-
dial glucose increments after weight loss are either un-
changed (oral glucose-tolerance test) or lower (meal-toler-
ance test), demonstrating that the effects of insulin to
stimulate glucose uptake in the postprandial state are mark-
edly improved. This is consistent with the enhanced glucose
disposal rates during the euglycemic clamp studies and fur-
ther demonstrates that the improved peripheral insulin re-
sistance measured during these clamp studies has a phys-
iologically relevant manifestation, i.e., lowered postprandial
plasma glucose levels. Just as hyperglycemia potentiates
insulin secretion, it also potentiates glucose uptake, and it is
quite notable that after weight loss the system resets itself
so that postprandial increments of both insulin and glucose
are fairly similar to the values before weight loss.
Because insulin therapy can ameliorate the insulin resis-
tance in alloxan-diabetic dogs40 as well as in NIDDM sub-
DIABETES, VOL. 35, SEPTEMBER 1986
jects,324142 it is conceivable that the postbinding defect in
insulin action that characterizes the untreated diabetic state
results from insulin deficiency. However, our study does not
support this hypothesis because peripheral insulin levels did
not increase after treatment, despite marked improvement of
insulin resistance. This raises the possibility that hypergly-
cemia itself leads to insulin resistance, possibly through long-
term effects impairing glucose transport system activity.
Indirect support for this comes from our previous studies
showing that the magnitude of the in vivo postreceptor
defect20 as well as the in vitro decrease in glucose transport
activity37 is closely correlated with the height of the fasting
plasma glucose concentration in subjects with NIDDM. An
additional possibility is that elevated free fatty acid concen-
trations contribute to the pre-weight-reduction insulin-re-
sistant state. According to the "glucose fatty-acid cycle"
(Randle hypothesis), an inverse relationship exists between
circulating free fatty acid levels and insulin-mediated glucose
disposal.43 It has recently been directly demonstrated that
artificial elevation of free fatty acid levels in normal humans
results in reduced insulin-stimulated glucose disposal rates.44
By inference, the reduction of free fatty acid levels after
weight loss (see Table 1) could lead to the opposite effect,
with an improvement in peripheral insulin action.
Our studies are also quite relevant to an understanding of
the pathogenesis of hyperglycemia in NIDDM. Thus, the fact
that plasma glucose levels were markedly reduced, despite
no change in plasma insulin levels at the same time that basal
HGO and peripheral insulin resistance were improved, dem-
onstrates that the proximate cause of the hyperglycemia in
the untreated state was the elevated HGO rates and the
peripheral insulin resistance. As previously reviewed,45 fast-
ing hyperglycemia is predominantly due to elevated rates of
basal HGO, whereas postprandial hyperglycemia is mostly
due to decreased insulin-mediated glucose disposal. Thus,
the weight-reduction-mediated fall in basal HGO was the
major cause of reduced fasting glucose levels, whereas the
improved peripheral insulin action led to the enhanced post-
prandial glucose disposal. This line of reasoning should not
be construed to imply that impaired insulin secretion is un-
important to the pathogenesis of NIDDM. Clearly, many in-
dividuals with insulin resistance, due to obesity or other
causes, maintain relatively normal glucose homeostasis by
augmenting insulin secretion with the development of hy-
perinsulinemia. By analogy, it seems most likely that if NIDDM
subjects were able to mount a hyperinsulinemic fJ-cell re-
sponse, hyperglycemia could be largely or partly avoided,
even in the face of increased basal HGO and peripheral
insulin resistance. With this line of reasoning, when insulin
requirements increase due to advancing insulin resistance
and/or increased HGO, then NIDDM subjects (or those des-
tined to become diabetic) are unable to meet target tissue
demands because of restricted (3-cell function, allowing hy-
perglycemia to develop or worsen. With this scenario the
three metabolic defects—peripheral insulin resistance, im-
paired insulin secretion, and increased basal HGO—all work
in concert, resulting in the NIDDM state.
ACKNOWLEDGMENTS
We thank the laboratory staffs and nurses of the Special
Diagnostic and Treatment Unit at the San Diego Veterans
997
Administration Medical Center, the University of California,
San Diego, and the University of Colorado Clinical Research
Center for assistance; Paul Shragg, CLINFO system man-
ager, for statistical advice and assistance; and Elizabeth Mar-
tinez for excellent secretarial assistance in preparing the
manuscript.
This work was supported by funds from the Medical Re-
search Council of Canada and the Medical Research Service
of the Veterans Administration, NIAMDD Grants AM-26180
and AM-31317, NIH Clinical Research Center Branch Grants
RR-00051 and RR-00827, and a grant from the Cambridge
Quest Foundation.
Dr. Henry is the recipient of a Medical Research Council
of Canada Fellowship Award.
This work was presented in abstract form at the annual
meeting of the American Diabetes Association, Baltimore,
MD, June, 1985.
REFERENCES
1
Hadden, D. R., Montgomery, D. A. D., Skelley, R. J., Tremble, E. R.,
Weaver, J. A., Wilson, E. A., and Buchanan, K. D.: Maturity onset diabetes
mellitus: response to intensive dietary management. Br. Med. J. 1975; 3 : 2 7 6 -
78.
2
Bistrian, B. R., Blackburn, G. L , Flatt, J., Sizer, J., Scrimshaw, N. S.,
and Sherman, M.: Nitrogen metabolism and insulin requirements in obese
diabetic adults on a protein-sparing modified fast. Diabetes 1976; 2 5 : 4 9 4 -
504.
3
Genuth, S. M.: Insulin secretion in obesity and diabetes: an illustrative
case. Ann. Intern. Med. 1977; 87:714-16.
4 31
Savage, P. J., Bennion, L. J., and Bennett, P. K : Normalization of insulin
and glucagon secretion in ketosis-resistant diabetes mellitus with prolonged
diet therapy. J . Clin. Endocrinol. Metab. 1979; 4 9 : 8 3 0 - 3 3 .
5 32
Savage, P. J., Bennion, L. J., Flock, E. V., Nagulesparan, M., Mott, D.,
Roth, J., Unger, R. H., and Bennett, P. H.: Diet-induced improvement of ab-
normalities in insulin and glucagon secretion and in insulin receptor binding
in diabetes mellitus. J. Clin. Endocrinol. Metab. 1979; 48:999-1007.
6
Nagulesparan, M., Savage, P. J., Bennion, L. J., Unger, R. H., and
Bennett, P. H.: Diminished effect of caloric restriction on control of hypergly-
cemia with increasing known duration of type II diabetes mellitus. J. Clin.
Endocrinol. Metab. 1981; 5 3 : 5 6 0 - 6 8 .
7
Fitz, J. D., Sperling, E. M., and Fein, H. G.: A hypocaloric high-protein
diet as primary therapy for adults with obesity-related diabetes: effective long-
term use in a community hospital. Diabetes Care 1983; 6:328-33.
8
Bogardus, C , Ravussin, E., Robbins, D. C , Wolfe, R. R., Horton,
E. S., a n d Simms, E. A. H : Effects of physical training and diet therapy on
carbohydrate metabolism in patients with glucose intolerance and non-insulin-
dependent diabetes mellitus. Diabetes 1984; 33:311-18.
9 37
Hughes, T. A., Gwynne, J. T., Switzer, B. R., Herbst, C , and White,
G.: Effects of caloric restriction and weight loss on glycemic control, insulin
release and resistance, and atherosclerotic risk in obese patients with type II
diabetes mellitus. Am. J. Med. 1984; 77:7-17.
10
Beck-Nielsen, H., Pedersen, O., andSorensen, N.S.: Effects of dietary
changes on cellular insulin binding and in vivo insulin sensitivity. Metabolism
1980; 2 9 : 4 8 2 - 8 7 .
11
DeFronzo, R. A., Ferrannini, E., and Koivisto, V : New concepts in the
pathogenesis a n d treatment of noninsulin-dependent diabetes mellitus. A m .
J. Med. 1983; 74 (Suppl.):52-81.
12
Olefsky, J . , Reaven, G. M., and Farquhar, J. W.: Effects of weight
reduction on obesity. Studies of lipid and carbohydrate metabolism in normal
and hyperlipoproteinemic subjects. J. Clin. Invest. 1974; 5 3 : 6 4 - 7 6 . •
13
Kalkhoff, R. K., Kim, H. J., Cerletty, J., and Ferrou, C. A.: Metabolic
effects of weight loss in obese subjects. Diabetes 1971; 2 0 : 8 3 - 9 1 .
14
Kosaka, K., Hagura, R., Odagiri, R., Saito, F, and Kuzuya, T : Effect
of weight changes on serum insulin response in subjects with normal oral
glucose tolerance. J. Clin. Endocrinol. Metab. 1972; 3 5 : 6 5 5 - 5 8 .
15
Berkowitz, D.: Metabolic changes associated with obesity before and
after weight reduction. JAMA 1964; 187:399-403.
16
Stanik, S., and Marcus, M.: Insulin secretion improves following di-
etary control of plasma glucose in severely hyperglycemic obese patients.
Metabolism 1980; 2 9 : 3 4 6 - 5 0 .
17
Kosaka, K., Kuzuya, T., Akanuma, Y., and Hagura, R.: Increase in
insulin response after treatment of overt maturity-onset diabetes is independent
of the mode of treatment. Diabetologia 1980; 18:23-28.
18
Doar, J. W. H., Thompson, M. E., Wilde, C. E., and Sewell, P. F. J.:
Influence of treatment with diet alone on oral glucose-tolerance test and plasma
998
sugar and insulin levels in patients with maturity-onset diabetes mellitus. Lan-
cet 1975; 1:1263-66.
19
National Diabetes Data Group: Classification and diagnosis of dia-
betes mellitus and other categories of glucose intolerance. Diabetes 1979;
28:1039-57.
20
Kolterman, O. G., Gray, R. S., Griffin, J., Burstein, P., Insel, J., Scarlett,
J. A., and Olefsky, J. M.: Receptor and postreceptor defects contribute to the
insulin resistance in non-insulin-dependent diabetes mellitus. J. Clin. Invest.
1981; 68:957-69.
21
Chiasson, J. L , Liljenquist, J. E., Lacy, W. W., Jennings, A. S., and
Cherrington, A. D.: Gluconeogenesis: methodological approaches in vivo. Fed.
Proc. 1977; 3 6 : 2 2 9 - 3 5 .
22
Steele, R.: Influence of glucose loading and injected insulin on hepatic
glucose output. Ann. NY Acad. Sci. 1959; 82:420-30.
23
Ciaraldi, T. P., Kolterman, O. G., Siegel, J. A., and Olefsky, J. M.:
Insulin stimulated glucose transport in human adipocytes. Am. J. Physiol. 1979;
236:E621-25.
24
Desbuquois, B., a n d Aurbach, A. D.: Use of polyethylene glycol to
separate free a n d antibody-bound peptide hormones in radioimmunoassays.
J. Clin. Endocrinol. Metab. 1971; 3 3 : 7 3 2 - 3 8 .
25
Faloona, G. R., a n d Unger, R. H.: Methods of hormone radioimmu-
noassay. In G l u c a g o n . Jaffe, B. M., a n d Behrman, H. R., Eds. New York,
Academic, 1975:317-30.
26
D o w Chemical C o m p a n y : Triglycerides Determination. Midland, Ml,
1978.
27
Richmond, W.: Preparation a n d properties of a cholesterol oxidase
from Nocardia Sp. a n d its application to the enzymatic assay of total cholesterol
in serum. Clin. Chem. 1973; 19:1350-56.
28
Bowen, H. F, a n d Moorhouse, J. A.: Glucose turnover and disposal
in maturity-onset diabetes. J . Clin. Invest. 1973; 5 2 : 3 0 3 3 - 4 5 .
29
Best, J. D., J u d z e w i t s c h , R. G., Pfeifer, M. A., Beard, J. C , Halter,
J. B., and Porte, D., Jr.: The effect of chronic sulfonylurea therapy on hepatic
glucose production in non-insulin-dependent diabetes. Diabetes 1982;
31:333-38.
30
Revers, R. R., Fink, R., Griffin, J., Olefsky, J. M., and Kolterman,
O. G.: Influence of h y p e r g l y c e m i a o n insulin's in vivo effects in type II diabetes.
J. Clin. Invest. 1984; 7 3 : 6 6 4 - 7 2 .
Kolterman, O. G., Gray, R. S., Shapiro, G., Scarlett, J . A., Griffin, J.,
and Olefsky, J. M.: The acute a n d chronic effects of sulfonylurea therapy in
type II diabetes. Diabetes 1984; 3 3 : 3 4 6 - 5 4 .
Garvey, W. T., Olefsky, J. M., Griffin, J., H a m m a n , R. F, a n d Koiterman,
0. G.: The effect of insulin treatment on insulin secretion and insulin action in
type II diabetes mellitus. Diabetes 1985; 34:222-34.
33
Bar, R. S., G o r d e n , P., Roth, J., Kahn, C. R., a n d DeMeyts, P.: Fluc-
tuations in the affinity and concentration of insulin receptors on circulating
monocytes of obese patients. J. Clin. Invest. 1976; 58:1123-35.
34
Kolterman, 0. G., Saekow, M., and Olefsky, J. M.: The effects of acute
and chronic starvation on insulin binding to isolated human adipocytes. J. Clin.
Endocrinol. Metab. 1979; 48:836-42.
35
Pedersen, 0., Hjollund, E., and Sorensen, N. S.: Insulin receptor bind-
ing and insulin action in human fat cells: effects of obesity and fasting. Me-
tabolism 1982; 31:82-93.
36
Rizza, R. A., Mandarino, L. J., and Gerich, J. E.: Mechanism and
significance of insulin resistance in noninsulin-dependent diabetes mellitus.
Diabetes 1981; 30:990-95.
Ciaraldi, T. P., Kolterman, 0. G., Scarlett, J. A., Kao, M., and Olefsky,
J. M.: Role of glucose transport in the postreceptor defect of non-insulin-
dependent diabetes mellitus. Diabetes 1982; 31:1016-22.
38
Halter, J. B., Graf, R. J., a n d Porte, D., Jr.: Potentiation of insulin
secretory responses b y p l a s m a g l u c o s e levels in man: evidence that hyper-
glycemia in diabetes c o m p e n s a t e s for impaired glucose potentiation. J. Clin.
Endocrinol. Metab. 1979; 48:946-54.
39
Ward, W. K., Bolgiano, D. C , McKnight, B., Halter, J. B., a n d Porte,
D., Jr.: Diminished B cell secretory c a p a c i t y in patients with noninsulin-de-
pendent diabetes mellitus. J . Clin. Invest. 1984; 7 4 : 1 3 1 8 - 2 8 .
40
Reaven, G. M., S a g e m a n , W. S., a n d Swenson, R. S.: Development
of insulin resistance in normal d o g s following alloxan-induced insulin defi-
ciency. Diabetologia 1977; 13:459-62.
41
Scarlett, J. A., Gray, R. S., Griffin, J., Olefsky, J. M., and Kolterman,
0. G.: Insulin treatment reverses the insulin resistance of type II diabetes
mellitus. Diabetes Care 1982; 5:353-63.
42
Scarlett, J. A., Kolterman, 0. G., Ciaraldi, T. P., Kao, M., and Olefsky,
J. M.: Insulin treatment reverses the postreceptor defect in adipocyte 3-0-
methylglucose transport in type II diabetes mellitus. J. Clin. Endocrinol. Metab.
1983; 56:1195-201.
43
Randle, P. J., Garland, P. B., Hales, C. N., and Newsholme, E. A.:
The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic
disturbances of diabetes mellitus. Lancet 1963; 1:785-89.
44
Ferrannini, E., Barrett, E. J., Bevilacqua, S., and DeFronzo, R. A.:
Effect of fatty acids on glucose production and utilization in man. J. Clin. Invest.
1983; 72:1737-47.
45
Olefsky, J. M.: Introduction: pathogenesis of insulin resistance and
hyperglycemia in NIDDM. Am. J. Med. 1985; 79:1-11.
DIABETES, VOL. 35, SEPTEMBER 1986