Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905
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ABSTRACT |
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People with type 2 diabetes have defects in both
- and
-cell function. To determine whether lack of suppression of
glucagon causes hyperglycemia when insulin secretion is impaired but
not when insulin secretion is intact, twenty nondiabetic subjects were
studied on two occasions. On both occasions, a "prandial" glucose
infusion was given over 5 h while endogenous hormone secretion was
inhibited. Insulin was infused so as to mimic either a nondiabetic (n = 10) or diabetic
(n = 10) postprandial profile.
Glucagon was infused at a rate of 1.25 ng · kg
1 · min
1,
beginning either at time zero to
prevent a fall in glucagon (nonsuppressed study day) or at 2 h to
create a transient fall in glucagon (suppressed study day). During the
"diabetic" insulin profile, lack of glucagon suppression resulted
in a marked increase (P < 0.002) in
both the peak glucose concentration (11.9 ± 0.4 vs. 8.9 ± 0.4 mmol/l) and the area above basal of glucose (927 ± 77 vs. 546 ± 112 mmol · l
1 · 6 h) because of impaired (P < 0.001)
suppression of glucose production. In contrast, during the
"nondiabetic" insulin profile, lack of suppression of glucagon
resulted in only a slight increase (P < 0.02) in the peak glucose concentration (9.1 ± 0.4 vs. 8.4 ± 0.3 mmol/l) and the area above basal of glucose (654 ± 146 vs. 488 ± 118 mmol · l
1 · 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can
cause substantial hyperglycemia when insulin availability is limited,
therefore implying that inhibitors of glucagon secretion and/or
glucagon action are likely to be useful therapeutic agents in such individuals.
glucose production; glucose disappearance; postprandial hypoglycemia; type 2 diabetes; glucagon; insulin
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INTRODUCTION |
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IN NONDIABETIC INDIVIDUALS, insulin concentrations promptly increase and glucagon concentrations promptly decrease after carbohydrate ingestion (1, 6, 21). These hormonal changes act in concert to minimize the postprandial rise in glucose. In contrast, people with type 2 diabetes have defects in both insulin and glucagon secretion (1, 6, 21). As the severity of diabetes increases, insulin secretion decreases, with peak concentrations typically not occurring until 1-2 h after the start of a meal (6, 21). In addition, glucagon concentrations either are not suppressed or, paradoxically, may even increase (6, 21). The relative contribution of these concomitant alterations in insulin and glucagon secretion to postprandial hyperglycemia is currently not known.
Numerous studies have demonstrated that glucagon is a potent stimulus of glucose production, with the magnitude of the effect being dependent on the prevailing insulin concentration (10, 11, 17, 18, 26, 30). We have previously shown that lack of postprandial suppression of glucagon in the presence of relative insulin deficiency can impair glucose tolerance in people with type 1 diabetes (9). On the other hand, we (12) and others (16, 27) also have reported that lack of suppression or even a three- to fourfold increase in glucagon does not alter glucose tolerance in nondiabetic humans under conditions in which insulin secretion is not inhibited. Taken together, these observations suggest either that lack of suppression of glucagon is important only in the presence of insulin deficiency, or that the sensitivity to glucagon differs in nondiabetic and type 1 diabetic subjects (23). Because a variety of agents that either inhibit glucagon secretion (8, 25, 32) or antagonize glucagon action (24, 28, 34-36) are currently being developed as therapeutic agents for the treatment of diabetes, it is important to distinguish between these two possibilities. The former explanation would imply that inhibition of glucagon would provide little added benefit if early postprandial insulin secretion also is normalized (e.g., as occurs with glucagon-like peptide-1), whereas the latter explanation would imply that the response to a glucagon antagonist would primarily be determined by the degree of hepatic sensitivity to glucagon.
The present experiments therefore were undertaken to test the hypotheses that lack of glucagon suppression impairs glucose tolerance in the presence of relative insulin insufficiency but does not do so in the presence of insulin sufficiency. To test these hypotheses, we studied nondiabetic subjects under conditions in which suppression or lack of suppression of glucagon was produced by means of somatostatin and appropriately timed glucagon infusions. Responses were determined in the presence of systemic insulin concentrations that mimicked those typically observed in either nondiabetic or type 2 diabetic subjects after food ingestion (1, 6, 21). We report that lack of suppression of glucagon has little if any impact on glucose tolerance when accompanied by a prompt rise in insulin (i.e., such as occurs in nondiabetic individuals) but causes substantial hyperglycemia when the rise in insulin concentration is delayed and decreased (i.e., such as occurs in people with type 2 diabetes mellitus).
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METHODS |
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Subjects.
After approval from the Mayo Institutional Review Board, twenty healthy
nondiabetic subjects gave written consent to participate in the study.
All subjects were in good health, had normal blood pressure, and were
at stable weight. None regularly engaged in vigorous exercise or
regularly took medications other than oral contraceptive pills,
estrogen, or thyroxin replacement. Except for two subjects, who were
adopted and therefore could not provide family history, none had a
family history of diabetes mellitus. The characteristics of the
subjects are shown in Table 1.
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Experimental design.
All subjects were studied on two occasions separated by 5 days.
Subjects were admitted to the General Clinical Research Center at 1700 on the evening before each study. After ingestion of a standard 10 kcal/kg meal (50% carbohydrate, 15% protein, 35% fat) between 1730 and 1800, subjects remained fasting (with the exception of occasional
sips of water) until the end of the study. At 0600 on the following
morning, an 18-gauge catheter was inserted into a forearm vein and used
for all infusions. A cannula also was inserted retrogradely into a
dorsal vein of the other hand. The hand was then placed in a heated
Plexiglas box and maintained at a temperature of ~55°C to allow
sampling of arterialized venous blood.
Analytic techniques.
Arterialized plasma samples were placed on ice, centrifuged at 4°C,
separated, and stored at 20°C until assay. Plasma C-peptide and glucagon concentrations were measured by radioimmunoassay by use of
reagents purchased from Linco Research (St. Louis, MO). Plasma insulin
and growth hormone concentrations were measured using reagents provided
by Beckman Laboratories (Chaska, MN). Plasma
[14C]glucose and
[6-3H]glucose specific
activities were determined as previously described (3, 20). Body
composition was measured by dual-energy X-ray absorptiometry (DEXA
scanner; Hologic, Waltham, MA). Glucose and lactate concentrations were
measured using a Yellow Springs glucose and lactate analyzer (Yellow
Springs Instruments, Yellow Springs, OH).
Calculations. Glucose specific activities were smoothed using the method of Bradley et al. (4). Glucose appearance and disappearance were calculated using the non-steady-state equations of Steele et al. (29), in which the actual tracer infusion rate for each interval was used in the calculation. The volume of distribution of glucose was assumed to equal 200 ml/kg, and the pool correction factor was assumed to be 0.65 (5). Endogenous glucose production was determined by subtracting the glucose infusion rate from the tracer-determined rate of glucose appearance. All rates of infusion and turnover were expressed per kilogram of lean body mass. The fraction of glucose derived from 14CO2 was calculated by dividing the plasma [14C]glucose specific activity by breath 14CO2 specific activity (20).
Statistical analysis.
Data in Table 1, Figs. 1-7, and the text are expressed as means ± SE. Values observed from 30 to 0 min on each study day were meaned for each individual and considered as basal. Area above or below
basal was calculated using the trapezoidal rule. If a study was
terminated due to hypoglycemia (defined as a glucose concentration of
<3.3 mmol/l), the data up to that time were used for calculation of
area under the curve on both study days. Two-tailed paired and
nonpaired Student's t-tests were used
to test for within- and between-group differences. A
P value of <0.05 was considered to
be statistically significant.
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RESULTS |
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Plasma insulin concentrations.
Insulin concentrations were comparable both before and during the
insulin infusions on the glucagon-suppressed and glucagon-nonsuppressed study days (Fig. 1). Insulin concentrations
peaked earlier (33 ± 6 vs. 125 ± 5 min) during the nondiabetic
than during the diabetic insulin profile.
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Plasma glucagon concentrations.
Glucagon concentrations did not differ during the baseline period
(i.e., from 30 to 0 min) or during the final 4 h of the experiment on the glucagon-suppressed and glucagon-nonsuppressed days
(Fig. 2). However, glucagon concentrations
were lower (P < 0.001) during the
first 2 h of the glucagon-suppressed study day than during the
glucagon-nonsuppressed study day in both the nondiabetic (125 ± 7 vs. 77 ± 4 ng/l) and diabetic (110 ± 7 vs. 59 ± 7 ng/l)
insulin profiles.
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Plasma C-peptide and growth hormone concentrations.
Plasma C-peptide concentrations did not differ during either insulin
infusion on either study day, with somatostatin producing prompt and
equal suppression of insulin secretion on all occasions (Fig.
3). Growth hormone concentrations also did
not differ on the suppressed and nonsuppressed study days.
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Plasma glucose concentrations.
Fasting plasma glucose concentrations were comparable in both groups on
both study days (Fig. 4). Plasma glucose
concentrations rose during nondiabetic insulin and
prandial glucose infusions, reaching a peak at ~30 min. Both the peak
glucose concentration (9.1 ± 0.4 vs. 8.4 ± 0.3 mmol/l) and the
area above basal of glucose (654 ± 146 vs. 488 ± 118 mmol · l1 · 6 h) were slightly, but significantly (P < 0.05) greater on the glucagon-nonsuppressed than the
glucagon-suppressed study days. To avoid the confounding effects of
glucose counterregulation, the study was terminated before 300 min if
glucose concentration fell below 3.3 mmol/l. Glucose fell below 3.3 mmol/l in three subjects on the glucagon-nonsuppressed study day (one
at 135 min and two at 210 min) but in no subjects on the
glucagon-suppressed study day.
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Glucose disappearance.
Plasma glucose concentration is determined by the balance between the
rates of glucose appearance and disappearance. The increase in glucose
disappearance above basal did not differ during either the nondiabetic
(3.27 ± 0.38 vs. 3.10 ± 0.27 mmol · kg1 · 6 h) or the diabetic (3.31 ± 0.29 vs. 2.79 ± 0.29 mmol · kg
1 · 6 h) insulin profiles on the glucagon-nonsuppressed and
glucagon-suppressed study days (Fig. 5).
Rates of glucose disappearance during the first 2 h of study, if
anything, tended to be greater on the glucagon-nonsuppressed than the
glucagon-suppressed study days, with the difference being more evident
during the diabetic (2.33 ± 0.13 vs. 1.97 ± 0.16 mmol · kg
1 · 2 h) than the nondiabetic (2.40 ± 0.22 vs. 2.23 ± 0.01 mmol · kg
1 · 2 h) insulin profile, indicating that the higher prevailing glucose
concentrations did not result from lower rates of disappearance. Although glucose disappearance during the first 2 h of the nondiabetic and diabetic insulin profiles was similar on the nonsuppressed study
days, this occurred in the presence of markedly different plasma
glucose concentrations. This suggests that the rapid increase in
insulin was primarily responsible for the increase in glucose clearance
during the first 2 h of the nondiabetic study day, whereas the higher
glucose concentrations were primarily responsible for the increase in
glucose clearance on the diabetic study day.
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Endogenous glucose production.
The combined effect of the nondiabetic insulin profile and the
concomitant rise in glucose concentrations resulted in prompt inhibition of endogenous glucose production, followed by a subsequent rise on both the glucagon-nonsuppressed and glucagon-suppressed study
days (Fig. 6). Although total integrated
rates over the entire period of study did not differ on the
glucagon-nonsuppressed and glucagon-suppressed study days (2.98 ± 0.36 vs. 2.89 ± 0.26 mmol · kg1 · 6 h), endogenous glucose production was less inhibited
(P < 0.01) during the first 2 h
(i.e., when glucagon concentrations differed) of the
glucagon-nonsuppressed than the glucagon-suppressed study days
(
0.57 ± 0.15 vs.
1.08 ± 0.06 mmol · kg
1 · 2 h).
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Incorporation of
14CO2 into
glucose.
The percentage of glucose derived from
14CO2
decreased to a comparable extent during the first 2 h of the
nondiabetic and diabetic insulin profiles on both the
glucagon-nonsuppressed and glucagon-suppressed study days (Fig.
7), implying similar suppression of
gluconeogenesis. Thereafter, incorporation of
14CO2
into glucose increased, with the magnitude of the increase being
equivalent during the latter portion of the diabetic insulin profile
but greater (P < 0.05) during the
latter portion of the nondiabetic insulin profile on the
glucagon-nonsuppressed than the glucagon-suppressed day (13.2 ± 1.4 vs.
17.6 ± 1.7% during the last 2 h).
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Plasma lactate concentrations. Plasma lactate concentrations did not differ before or during the nondiabetic and diabetic insulin profiles on either day (data not shown).
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DISCUSSION |
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People with type 2 diabetes have abnormalities in both - and
-cell function (1, 6, 21). Carbohydrate ingestion either fails to
suppress or causes a paradoxical increase in plasma glucagon concentrations (1, 6, 21). In addition, insulin secretion decreases
with increasing severity of diabetes, with peak postprandial insulin
concentrations becoming progressively decreased and delayed (1, 6, 21).
The present studies demonstrate that in the absence of an appropriately
timed increase in insulin (i.e., during the diabetic insulin profile),
lack of suppression of glucagon can cause substantial hyperglycemia.
Lack of suppression of glucagon resulted in an almost twofold increase
in the integrated glycemic response and a 3.0 mmol/l (~50 mg/dl)
increase in the peak glucose concentration. Lack of suppression of
glucagon caused hyperglycemia by impairing glucose- and insulin-induced
inhibition of endogenous glucose production. In contrast, lack of
suppression of glucagon only had a minimal effect on glucose tolerance
when insulin concentrations rapidly increased (i.e., during the
nondiabetic insulin profile). Of particular interest, suppression of
glucagon in itself was sufficient to restore glucose concentrations
observed during the diabetic insulin profile to almost the same levels
as were observed during the nondiabetic insulin profile. These data
suggest that lack of suppression of glucagon, by impairing suppression
of endogenous glucose production, potentially can contribute to
postprandial hyperglycemia in people with limited insulin secretory
reserve (e.g., people with type 2 diabetes). They also imply that
inhibitors of glucagon secretion and/or glucagon action are likely to
be useful therapeutic agents in such individuals.
Numerous in vitro and in vivo studies have emphasized the importance of the portal venous glucagon-to-insulin ratio in the regulation of hepatic glucose production (10, 17, 30). The observation that lack of suppression of glucagon caused greater hyperglycemia when the increase in insulin concentrations was delayed (i.e., the diabetic insulin profile) than when there was a prompt increase in insulin (i.e., the nondiabetic insulin profile) is consistent with this concept. As discussed earlier (9), the peripheral venous glucagon concentrations of ~150-160 ng/l present during the replacement glucagon infusions (i.e., from 0 to 300 min on the nonsuppressed days and from 121 to 300 min on the suppressed days) likely represented either no change or a slight increase in portal glucagon concentrations relative to those present before the somatostatin infusion. In this instance, it is highly probable that the tenfold rise in circulating insulin concentrations that occurred during the first 30 min of the nondiabetic insulin profile resulted in a substantial decrease in the portal venous glucagon-to-insulin ratio, regardless of whether or not glucagon was suppressed. Conversely, during the first 30 min of the diabetic insulin profile, peripheral insulin concentrations only increased from ~20 to ~60 pmol/l, and the C-peptide concentrations decreased threefold. This suggests that the portal venous insulin, and hence, the glucagon-to-insulin ratio, either stayed the same or increased slightly, depending on whether portal venous glucagon concentrations stayed the same or increased slightly. The transient increase in endogenous glucose production followed by a subsequent delay in suppression suggests the latter. This pattern is remarkably similar to that previously observed in people with type 2 diabetes when the dual-isotope technique was used to trace endogenous glucose production after ingestion of a meal (6, 20). Although in the past we have been concerned that the apparent paradoxical increase in glucose production was an artifact of tracer nonsteady state, the present studies suggest that this may not be the case. Instead, it may be due to a brief paradoxical increase in glucagon (21), resulting in a transient increase in the portal venous glucagon-to-insulin ratio. If so, then agents that inhibit glucagon secretion or antagonize glucagon action may be particularly effective in restoring the rate of suppression of postprandial glucose production in people with type 2 diabetes toward that observed in nondiabetic individuals.
In nondiabetic individuals, ingestion of carbohydrate results in a rise in glucose and insulin that in turn suppresses glucagon secretion (37). This is followed several hours later by an increase in glucagon secretion that accompanies the fall in glucose and insulin concentrations back toward basal levels. Inhibition of this late compensatory increase in glucagon secretion can cause late postprandial hypoglycemia (33). A similar phenomenon appears to have occurred in the present experiments. Infusion of the prandial glucose and nondiabetic insulin profiles on the glucagon-suppressed study day resulted in a nearly normal glycemic excursion, followed by a smooth return of glucose to basal levels. In contrast, although glucose concentrations peaked slightly higher on the glucagon-nonsuppressed day, the study had to be stopped early (i.e., 135-210 min) in three individuals because of a fall in glucose to a level below 3.3 mmol/l. As is evident in Fig. 6, this presumably resulted from the fact that the late compensatory increase in glucose production was blunted by the lack of a concomitant late increase in glucagon. This observation is consistent with previous studies showing that although the hepatic response to constant glucagon wanes with time, it continues to respond to a change in glucagon concentration regardless of when it occurs (10, 11, 26).
Persistent and inappropriately elevated insulin concentrations also can cause hypoglycemia. Late hypoglycemia was commonly observed with the diabetic insulin profile, with the study being stopped in three subjects on the glucagon-nonsuppressed and in five subjects on the glucagon-suppressed study day. This likely reflects the fact that the diabetic insulin profile resulted in slightly but persistently higher insulin concentrations during the latter part of the study. The higher insulin concentrations presumably blunted the compensatory increase in glucose production that accompanied the increase in glucagon concentration on the glucagon-suppressed day. Glucose production was even more blunted on the glucagon-nonsuppressed day. However, fewer individuals developed hypoglycemia on the glucagon-nonsuppressed day because their glucose concentration was falling from a far higher peak. These data highlight a potential problem that may occur with the use of glucagon antagonists to treat diabetes. The onset of action of these agents will need to coincide with the period of time during which glucose concentrations are rising, and the duration of action will need to be carefully matched to insulin availability. If not, lower peak postprandial glucose concentrations may be achieved at the expense of a greater frequency of hypoglycemia occurring 4-5 h after meal ingestion.
The present experiments only measured the rate of glucose release into the systemic circulation. They therefore cannot determine the site of origin of the glucose. However, recent studies using the renal vein catheterization technique indicate that glucagon has little if any effect on glucose production by the kidney, suggesting that glucagon primarily acts by modulating hepatic glucose release (31). Glucose released by the liver originates from either glycogenolysis or gluconeogenesis. As discussed in detail elsewhere (20), incorporation of 14CO2 into glucose measures flux through the pyruvate carboxylase pathway. It therefore primarily traces new glucose synthesis from pyruvate, lactate, and alanine. Plasma lactate concentrations did not differ, and the percentage of glucose derived from 14CO2 was equally inhibited during the initial portion of the nondiabetic and diabetic insulin profiles on both the glucagon-suppressed and glucagon-nonsuppressed study days. This implies comparable inhibition of gluconeogenesis on all occasions and that the observed difference in endogenous glucose production on the suppressed and nonsuppressed study days was primarily due to differences in glycogenolysis. Of note, the percent incorporation of 14CO2 into glucose appeared to increase more rapidly during the latter portion of the nondiabetic insulin profile on the nonsuppressed study day, implying that glucagon exerted a late stimulatory effect on gluconeogenesis. This pattern was not observed during the diabetic insulin profile, presumably because of the higher plasma insulin concentrations that were present over this interval. These observations are consistent with reports by Cherrington et al. (7) that glucagon causes a time-dependent increase in gluconeogenesis that is more evident in the presence of low compared with high insulin concentrations. However, this post hoc finding needs to be interpreted with caution, because incorporation of 14CO2 into glucose only provides a qualitative estimate of gluconeogenesis and because the specific activity within the hepatic oxaloacetate pool is not known. Furthermore, the contribution of glycerol to gluconeogenesis is not measured with this technique (20). However, because the dilution within the oxaloacetate pool appears to remain relatively constant over a wide range of metabolic conditions (14), and because glucagon does not alter either lipolysis (13) or intrahepatic glycerol extraction (19), any error is likely to be small.
Only a single diabetic and nondiabetic insulin profile was evaluated.
Although insulin secretion varies considerably in diabetic individuals,
the pattern of insulin concentration that we chose to create (i.e.,
decreased and delayed) closely mimics that commonly observed after food
ingestion in people with moderately severe type 2 diabetes mellitus (1,
6, 21). On the other hand, people with a lesser impairment in -cell
function frequently have postprandial insulin concentrations that are
intermediate between those produced by the nondiabetic and diabetic
insulin profiles (6). We anticipate that effects of lack of suppression of glucagon in such individuals also would be intermediate between those observed in the present experiments with the two insulin profiles. We studied lean, healthy, nondiabetic subjects. We did so
because we wished to evaluate whether glucagon's effect on the liver
was dependent on the time course of change of plasma insulin
concentrations. We chose not to study individuals who were markedly
insulin resistant (e.g., severely obese type 2 diabetic subjects),
because the impact of differences in insulin availability may be moot
under conditions in which insulin has little if any biological effect.
Furthermore, we have previously shown that hepatic sensitivity to
glucagon does not differ in nondiabetic and type 2 diabetic subjects
(22). Nevertheless, future studies in people with type 2 diabetes with
varying degrees of insulin resistance will be of considerable interest,
because these are the individuals in whom glucagon antagonists are
likely to be used. Finally, because these experiments were performed in
humans, insulin and glucagon were infused into the systemic rather than the portal venous circulation. We doubt whether this substantially influenced the outcome, since glucagon is not known to have any effects
on peripheral tissues and because portal and peripheral insulin
infusion appears to have comparable effects on glucose production under
conditions in which glucagon secretion is controlled (15). Perhaps more
importantly, from the perspective of the present experiments,
endogenous insulin secretion was equally inhibited by somatostatin,
insuring equivalent portal venous insulin concentrations on the
glucagon-suppressed and glucagon-nonsuppressed study days.
In summary, the present experiments demonstrate that lack of suppression of glucagon causes marked hyperglycemia under conditions of relative insulin insufficiency. Conversely, suppression of glucagon substantially improves glucose tolerance, even though the pattern of insulin availability remains abnormal (i.e., mimicking that observed in people with type 2 diabetes). Lack of suppression of glucagon minimally alters glucose tolerance when insulin concentrations rapidly rise, once again confirming the concept that an increase in the portal venous insulin-to-glucagon ratio inhibits endogenous glucose production regardless of the absolute glucagon concentration. Although these experiments suggest that agents that either inhibit glucagon secretion or antagonize glucagon action may result in a considerable improvement in glycemic control in people with diabetes, they also introduce a note of caution, because they lend further support to results in the report of Tse et al. (33) that prolonged suppression of glucagon may increase the risk of late postprandial hypoglycemia. Therefore, it is likely that ability to appropriately craft the rapidity of onset and offset of such agents will determine whether their benefits will outweigh their risks.
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ACKNOWLEDGEMENTS |
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We thank C. Etter, T. Madson, and B. Dicke for technical assistance; M. Davis for assistance in the preparation of the manuscript; and the staff of the Mayo General Clinical Research Center for assistance in performing the studies.
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FOOTNOTES |
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This study was supported by the National Institutes of Health (DK-29953 and RR-00585) and the Mayo Foundation. Dr. P. Shah was supported in part by a research grant from Novo-Nordisk.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for correspondence and reprint requests: R. A. Rizza, Endocrine Research Unit, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905.
Received 19 January 1999; accepted in final form 15 April 1999.
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