Physiological Increase in Plasma Leptin Markedly Inhibits Insulin Secretion In Vivo
Jane A. Cases,
Ilan Gabriely,
Xiao Hui Ma,
Xiao Man Yang,
Tamar Michaeli,
Norman Fleischer,
Luciano Rossetti, and
Nir Barzilai
From the Diabetes Research and Training Center and the Division of
Endocrinology (J.A.C., I.G., X.H.M., X.M.Y., N.F., L.R., N.B.), Department of
Medicine, and the Department of Molecular Pharmacology (T.M.), Albert Einstein
College of Medicine, Bronx, New York.
Address correspondence and reprint requests to Nir Barzilai, MD, Division of
Endocrinology, Department of Medicine, Belfer Bldg. #701, Albert Einstein
College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail:
barzilai{at}aecom.yu.edu
.
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ABSTRACT
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The demonstration of leptin receptors on the pancreatic ß-cells
suggests the possibility of direct actions of leptin on insulin secretion. In
vitro studies on islets or perfused pancreas and ß-cell lines produced
inconsistent results. We performed an in vivo study to distinctly examine
whether leptin has an effect on glucose-stimulated insulin secretion. Young
chronically catheterized Sprague-Dawley rats (n = 28) were subjected
to a 4-h hyperglycemic clamp study (
11 mmol/l). At minute 120 to 240,
rats were assigned to receive either saline or leptin (0.1, 0.5, and 5 µg
· kg-1 · min) infusion. Leptin decreased plasma
insulin levels abruptly, and an approximately twofold decrease in plasma
insulin levels compared with saline control was sustained over the 2 h of the
study (14.8 ± 5.8 vs. 34.8 ± 2.6 ng/ml with leptin and saline
infusion, respectively, P < 0.001). Moreover, a dose-dependent
decrease in plasma insulin levels was noted (r = -0.731, P
< 0.01). Since milrinone, an inhibitor of cAMP phosphodiesterase (PDE) 3,
did not reverse the effect of leptin on glucose-induced insulin secretion, its
action may be independent of PDE3. These findings suggest that acute
physiological increase in plasma leptin levels acutely and significantly
inhibits glucose-stimulated insulin secretion in vivo. The site of leptin
effects on insulin secretion remains to be determined.
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INTRODUCTION
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Leptin, a 167-amino acid product of the ob gene and predominantly
produced by and secreted from adipose tissue
(1), plays an important role in
the central nervous system's regulation of food intake influencing body
weight, energy expenditure, and adiposity
(2). Leptin action has also
been reported in peripheral tissues such as fat, muscle, and liver
(3,4).
The demonstration of the long form of leptin receptor (ObRb) mRNA in rat
islets
(5,6)
also supports the possibility of direct actions of leptin on pancreatic
ß-cells. This last observation, coupled with the critical role of insulin
in metabolism, has led to multiple studies of the effect of leptin on insulin
secretion mainly in vitro. Leptin clearly reduces insulin secretion in
isolated pancreatic ß-cells
(7,8)
and perfused pancreas (7) of
ob/ob mice that do not produce leptin. However, acute administration
of leptin on insulin secretion has produced divergent results in normal
rodents. In isolated islets from rat or mouse, or perfused rat pancreas,
leptin has been reported to stimulate insulin secretion
(9), to have no effect
(10,11,12),
and to have biphasic effects
(13), depending on dose.
However, a number of studies have also demonstrated that leptin inhibits
insulin release
(14,15,16,17).
In whole-animal studies, acute leptin administration decreases basal insulin
levels, though this may have been due to increased insulin sensitivity
(18). One proposed local
mechanism for leptin inhibition of insulin secretion is through its activation
of phosphodiesterase (PDE) 3B. Static incubation in HIT-T15 cells demonstrated
the reversal of leptin effects on insulin secretion by agents such as
milrinone, a PDE3 inhibitor
(13).
The variable ways in which experiments have been performed make findings
difficult to compare and have left many uncertainties regarding optimal models
and conditions. This situation led us to design an in vivo study that
optimizes the conditions and limits the confounding variables for insulin
secretion. The main purpose of this study was to evaluate whether acute
increases in plasma leptin levels that are within the physiological range
affect glucose-stimulated insulin secretion in conscious rats and whether
activation of PDE3 by leptin could be implicated.
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RESEARCH DESIGN AND METHODS
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Animals. Three-month-old male Sprague-Dawley rats (n = 28)
(Charles River Laboratories, Wilmington, MA) were used for this study. Rats
were housed in individual cages and were subjected to a standard light (6:00
A.M. to 6:00 P.M.) and dark (6:00 P.M. to 6:00 A.M.) cycle. All rats were fed
ad libitum using regular rat diet that consisted of 64% carbohydrate, 30%
protein, and 6% fat with a physiological fuel value of 3.3-kcal/g food. One
week before the in vivo study, rats were anesthetized by inhalation of
methoxyflurane, and indwelling catheters were inserted in the right internal
jugular vein and in the left carotid artery. This method of anesthesia allows
fast recovery and normal food consumption after 1 day. The venous catheter
extended to the level of the right atrium, and the arterial catheter was
advanced to the level of the aortic arch. Recovery was continued until body
weight was within 3% of the preoperative weight (
4-6 days). Studies were
performed in awake, unstressed, chronically catheterized rats
(19,20).
Hyperglycemic clamp study. To demonstrate the in vivo effect of
leptin on insulin secretion, all rats were subjected to 4-h moderate
hyperglycemia (
11 mmol/l)
6 h postprandially. Briefly, 25% glucose
was infused intravenously to raise the plasma glucose concentration acutely to
11 mmol/l. The glucose infusion rate was then varied to maintain the
plasma glucose concentration at this level for 240 min. The first 120 min of
the clamp study was maintained before the infusion of either saline or leptin
to avoid the confounding effects of the acute increases in insulin levels
during the first phase of insulin secretion and achieve similar levels of
glucose-stimulated plasma insulin levels.
Leptin study. At minute 120, rats were assigned to receive either
saline (1 ml/h, n = 5, control) or leptin infusion for an additional
2 h. Leptin was infused as primed (0.5, 2.5, and 25 µg ·
kg-1 · min for 2 min) continuous infusion at 0.1 (L0.1;
n = 4), 0.5 (L0.5; n = 4), and 5 µg ·
kg-1 · min (L5; n = 4), respectively, to determine
the dose-response effect on plasma insulin levels.
Milrinone study. At minute 120 to 240, either milrinone (1, 3, and
28 µg · kg-1 · min, n = 7) or milrinone
(28 µg · kg-1 · min) + leptin (5 µg ·
kg-1 · min, L5) (n = 4) was infused. Plasma samples
for insulin were obtained at 10-min intervals throughout the study. Samples
were also obtained for determination of plasma leptin and free fatty acid
(FFA) concentrations. A solution (1:1 vol/vol) of
3.0 ml fresh blood
(obtained by heart puncture from a littermate of the test animal) and
heparinized saline (10 U/ml) was infused at a constant rate throughout the
study to prevent volume depletion and anemia. At the end of the clamp study,
rats were killed using 60 mg pentobarbital sodium/kg body wt i.v.
The study protocol was reviewed and approved by the Animal Care and Use
Committee of the Albert Einstein College of Medicine.
Analytical procedures. Plasma glucose was measured by the glucose
oxidase method (Glucose Analyzer II; Beckman Instruments, Palo Alto, CA) and
plasma insulin by radioimmunoassay using rat insulin standards. Plasma leptin
was assayed using the Linco leptin assay kit (Linco Research, St. Charles,
MO). Plasma nonesterified fatty acid concentrations were determined by an
enzymatic method with an automated kit according to the manufacturer's
specification (Waco Pure Chemical Industries, Osaka, Japan).
Terminology and calculations. To express insulin
sensitivity, metabolic clearance rate (MCR) of glucose was determined to
account for glucose uptake in a variety of nonmaximal stimulations of insulin
levels. Thus, the MCR of glucose was calculated as follows: MCR = glucose
infusion rate (GIR) divided by 2 plasma insulin.
Statistical analysis. The significance of group differences
was evaluated by the two-sample t test. Pearson correlation
coefficients were calculated to estimate the linear relationship between
variables. All values are presented as means ± SE. All statistical
analyses were performed using SPSS.
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RESULTS
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Leptin studies. Before the study, body weights (305 ± 10 g),
plasma glucose (8 ± 0.2 mmol/l), insulin (2.4 ± 0.4 ng/ml),
leptin (1.5 ± 0.1 ng/ml), and FFA (0.6 ± 0.04 meq/l) levels were
similar in all groups. During the clamp study, glucose levels were maintained
at similar levels (
11 mmol/l), and insulin levels continued to increase
throughout the saline (control) study and tended to reach a plateau after
minute 160 of hyperglycemia (Fig.
1), as previously demonstrated
(21). With variable infusion
rates of leptin (0.1, 0.5, and 5 µg · kg-1 · min),
a dose response could be assessed because averaged plasma leptin levels during
the clamps were 6 ± 1, 29 ± 5, and 261 ± 4 ng/ml
(P < 0.01 between all). These levels were demonstrated 10 min
after the primed infusion of leptin. Plasma insulin levels (averaged for the
final 120 min of the clamps) were abruptly and significantly decreased by
leptin and an approximately twofold decrease was sustained until the
termination of the study (14.8 ± 5.8 vs. 34.8 ± 2.6 ng/ml, with
leptin and saline infusion, respectively, P < 0.001)
(Table 1 and
Fig. 1). Moreover, decrease in
plasma insulin levels occurred earlier with L5 than with L0.1 (insulin levels
at 10 min of leptin infusion: 12 ± 3 vs. 18 ± 1 ng/ml with L5
vs. saline compared with insulin levels at 20 min 17 ± 2 vs. 22
± 2 ng/ml with L0.1 vs. saline, respectively, P < 0.05)
(Fig. 1). Intermediate results
were obtained at plasma leptin levels of
29 ng/ml
(Table 1). Figure 2 further demonstrates
leptin's dose-response effect and the significant inverse correlation between
leptin and plasma insulin levels (r = -0.731, P < 0.01).
Of note,
70% of leptin inhibition occurred with the lowest infusion rate
that increased leptin levels by only approximately threefold. Leptin infusion
significantly decreased GIR by
30% in all groups compared with saline
(P < 0.05). However, when GIR was further expressed in terms of
the MCR of glucose (GIR/plasma insulin), this remained unchanged in all groups
compared with saline (Table 1).
These data indicate no change in insulin sensitivity during this short
experimental period.

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FIG. 1. Effect of acute leptin infusion on plasma insulin levels. Log plasma
leptin (A) and plasma insulin (B) levels were measured
during hyperglycemic clamp ( 11 mmol/l) study from 0 to 240 min in rats
receiving intravenous infusion at minute 120 to 240 (arrow) of saline
(control; 1 ml/h) or leptin (L0.1; 0.1 µg · kg-1 ·
min and L5; 5 µg · kg-1 · min).
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FIG. 2. Dose-response effects of leptin on plasma insulin levels. Plasma insulin
and leptin levels are expressed as mean values from 180 to 240 min (P
< 0.01).
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Milrinone study. Plasma insulin levels increased promptly upon
infusion of milrinone during the first 10 min (insulin: 31 ± 6 vs. 18
± 1 ng/ml, with milrinone and saline respectively, P <
0.01) (Fig. 3). Surprisingly,
the stimulatory effect of milrinone lasted only for 30 min and was
subsequently followed by a decrease in plasma insulin levels. This may be
explained by a direct effect of milrinone on insulin secretion, glucose
uptake, or other unrelated pathway by which milrinone may influence glucose
homeostasis. Co-infusion of milrinone with L5 also resulted in an abrupt
increase in insulin secretion during the first 10 min (insulin: 27 ± 6
ng/m vs. saline; P < 0.01)
(Fig. 3), suggesting an initial
milrinone action. However, there was an acute decrease in plasma insulin
levels during the next 10 min, eventually reaching levels similar to those
noted with leptin infusion alone (insulin: 17 ± 3 vs. 13 ± 4
ng/ml, with milrinone + L5 and L5, respectively)
(Fig. 3).

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FIG. 3. Effect of milrinone, leptin, and milrinone with leptin on plasma insulin
levels. Plasma insulin levels were measured during a hyperglycemic clamp
( 11 mmol/l) study from 0 to 240 min in rats receiving intravenous
infusion at minute 120 to 240 (arrow) of milrinone (28 µg ·
kg-1 · min), leptin (L5; 5 µg · kg-1
· min), or milrinone + leptin (28 µg · kg-1
· min + 5 µg · kg-1 · min).
*P < 0.01 vs. milrinone alone.
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DISCUSSION
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This study demonstrates that acute increases in plasma leptin that are in a
physiologically relevant range suppress glucose-stimulated insulin secretion
in a dose-dependent manner.
Many in vitro studies on islets, perfused pancreas, and cell lines
demonstrated that leptin had an inhibitory effect on glucose-stimulated
insulin secretion
(14,15,16,17),
presumably through the ObRb receptor. However, leptin also has an important
role in the central regulation of food intake and energy expenditure and
possibly peripherally through autonomic output from the hypothalamus
(14,24).
Thus, the effects of leptin on ß-cell secretion may also work centrally.
Also, leptin may have other indirect effects on the function and action of
other hormones associated with the control of insulin secretion
(14).
Thus, in vivo studies may be most appropriate to examine the overall effect
of leptin on insulin secretion. This study was designed to optimize the in
vivo model of moderate hyperglycemia that will allow a valid interpretation of
the short-term in vivo effect of physiological increases in plasma leptin
levels on insulin secretion. Two hours of sustained hyperglycemia were
allotted before the infusion of leptin or saline to avoid the confounding
effects of the acute rise in insulin levels during the first phase of insulin
secretion and to obtain similar levels of insulin release in individual rats
before the infusion of leptin or saline at minute 120. Thereafter, the clamp
study was performed for an additional 2 h with either saline or leptin to
examine the ability of leptin to suppress insulin secretion. A 4-h study was
conceived to be adequate and appropriate since glucose-stimulated insulin
secretion was previously shown to continue to rise during most of this time
period (21).
This study also demonstrated that the inhibitory effect of leptin on
insulin secretion was immediate (
5-10 min after infusion) and dose
dependent (Fig. 2). We have
previously determined that leptin has no effect on the metabolic clearance
rate of insulin (4). This
abrupt inhibition of insulin secretion with leptin treatment is highly
suggestive that this effect is solely due to leptin action. The physiological
plasma leptin levels achieved to significantly suppress insulin secretion are
at levels found in mild obesity
(25) and with impaired glucose
tolerance (26). Whereas
Kieffer and Habener (27)
proposed that the chronic hyperleptinemic state of obesity may lead to a
relative insulin-deficient state (the adipoinsular axis hypothesis), this
short-term study cannot make valid implications regarding the effects of
chronic hyperleptinemia on insulin secretion. Hyperleptinemia for 14 days in
vivo and 3 days in vitro in normal and fa/fa rats suppressed insulin
secretion due to its lipopenic effect on islet cells
(28,29).
These observations (with leptin administration for several days) were
different from our study in which leptin effects had a rapid onset (within
minutes), and without changes in markers of lipid homeostasis.
Clues to direct cellular mechanisms by which leptin suppresses insulin
release come from earlier studies from ob/ob and db/db mouse
islets because both phenotypes result from the absence of leptin signaling.
One of the leading proposed mechanisms is through a reduction of cAMP by
leptin. This proposed mechanism was further supported when milrinone, a
selective inhibitor of PDE3, completely blocked the inhibitory effect of
leptin on glucose- or glucagon-like peptide 1-potentiated insulin secretion in
vitro (13). In an effort to
examine whether leptin action on glucose-induced insulin secretion is through
the activation of PDE3, we infused high doses of milrinone alone and milrinone
with high doses of leptin. The interpretation of these data is limited,
because milrinone increased insulin secretion initially, but with time insulin
secretion decreased (Fig. 3).
This could have been due to a downregulation of its own effect on insulin
secretion through the cAMP pathway. However, if we limit our discussion to the
first 60 min of milrinone infusion, leptin inhibited milrinone-induced insulin
secretion, an effect not readily explained by leptin activation of PDE3
(13).
Our study does not clearly demonstrate the site of leptin action on insulin
secretion. Although it was previously assumed from in vitro studies that the
metabolic effects of leptin are mediated locally through its tissue receptors,
such a notion had been challenged. In fact, many of leptin's effects were
demonstrated both centrally and peripherally. For example, it was demonstrated
that marked and acute hyperleptinemia modulated hepatic gene expression of the
gluconeogenic enzyme PEPCK and the rate of gluconeogenesis in vivo by
intracerebroventricular and intravenous routes
(4). The same results were
demonstrated in liver cell line
(30), suggesting that the
efferent pathway of leptin from the hypothalamus can influence peripheral
metabolism. Combined with negative results from examining the PDE3 system,
this example cautions us from concluding that the major effect of leptin on
insulin secretion is directly through its receptor on the ß-cells.
Finally, chronic hyperleptinemia in obesity is proposed to uncouple leptin
action on its receptor in the hypothalamus, thereby attenuating signal
transduction pathways that exert resistance to the hormone on satiety and
energy expenditure and metabolism
(2). If leptin resistance
extends to the effect of leptin on insulin secretion, then high leptin levels
may not contribute to the modulation of insulin secretion. However, this
hypothesis can be supported only by further studies on obese leptin-resistant
rodents compared with lean controls.
In summary, this is the first study designed to demonstrate the acute
effects of physiological increases in plasma leptin levels on the inhibition
of glucose-stimulated insulin secretion in vivo. Although our findings link
hyperleptinemia and decreased insulin secretion, the role of chronic effects
of hyperleptinemia with obesity leading to the transition to diabetes requires
further studies.
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ACKNOWLEDGMENTS
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This work was supported by grants from the National Institutes of Health
(KO8-AG00639 and R29-AG15003 to N.B. and R01-DK 45024 and ROI-DK48321 to L.R),
the American Diabetes Association, and by the Core laboratories of the Albert
Einstein Diabetes Research and Training Center (DK 20541). N.B. is a recipient
of the Paul Beeson Physician Faculty Scholar in Aging Award.
The authors wish to thank Bing Liu, Robin Squeglia, and Manju Suranja for
expert technical assistance.
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FOOTNOTES
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FFA, free fatty acid; GIR, glucose infusion rate; MCR, metabolic clearance
rate; ObRb, long-form splice variant of the leptin receptor; PDE,
phosphodiesterase.
Received for publication June 13, 2000
and accepted in revised form October 11, 2000
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