Leahy, MD
From the Research Division, Joslin Diabetes Center, and the Department of
Medicine, New England Deaconess Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Address correspondence and reprint requests to John L. Leahy, MD, Research
Division, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215.
992
I.L. LEAHY
When studying (3-cell function in NIDDM, a key question becomes: Are p-cells present in normal amounts,
and are they structurally intact? No single large study
has quantified p-cell mass in NIDDM, but there are several small studies that together comprise a sizable number of patients. Studies combining quantitative
morphometry with either histochemical (35,36) or immunocytochemical (18,19) techniques generally have
agreed that p-cell mass is modestly reduced compared
with that of age-matched control subjects. Stefan et al.
(37) reported no overall difference in 3 NIDDM subjects
and 13 nondiabetic subjects. However, their data also
show a decrease when the diabetic subjects are com-
993
TABLE 1
Pancreatic morphometry in obese and nonobese NIDDM and control subjects
Nonobese control (n = 7)
Nonobese NIDDM (n = 8)
Obese control (n = 4)
Obese NIDDM (n = 6)
0.21 0.10*
0.11 0.03*
0.40 0.02t
0.20 0.10t
Data are means SD. Statistical analysis was performed with Mann-Whitney U test. Morphometry was performed by point-counting method
of Weibel on whole pancreas minus pancreatic polypeptide lobe. NIDDM, non-insulin-dependent diabetes mellitus. Data taken from Kloppel
etal. (18).
*P < 0.001 nonobese control vs. nonobese NIDDM.
tP < 0.01 obese control vs. obese NIDDM.
994
J.L LEAHY
25
Fasting
Plasma
Insulin
(uU/ml)
20
l5
IO
5 -
L L
60
100
140
300
995
CO
2000
2000 g
m
o
1600
1600 5
o 1200
z
(/)
1200 F
E
Q_
in
CL
(/)
LJ
Of
73
800
800
CO
CO
"0
o
z
CO
400
400
50
100
150
200
250
CO
m
CO
300
ing it in eugylcemic subjects makes them glucose intolerant (83,84). A major confusion in the literature
concerns how to study glucose-induced insulin secretion. Intravenous glucose is the method of choice. In
contrast, oral glucose is an integrated measure of multiple effects on insulin secretion (changing glucose level,
glucose absorption, gut hormones, cephalic-induced insulin release) (16,82). As such, oral glucose does not
only assess P-cell glucose responsiveness, which may
explain why divergent results have at times been obtained with oral and intravenous glucose.
In the late 1960s, it was discovered that insulin release to intravenous glucose was delayed in subjects
with NIDDM (85-88). In quantitative terms, the response was also reduced when hyperglycemia was factored in (82,89). The reason for the delay was because
the first phase was missing (Fig. 4). By the time the
fasting blood glucose level reached 6.4 mM, no trace
of a first phase could be found (90). Paralleling the inability of glucose to stimulate insulin secretion, a lowered glucose level does not suppress insulin output (91).
It would be predicted, based on what we know about
the importance of the first phase, that losing it should
impair the ability to clear a bolus of intravenous glucose.
However, what about glucose homeostasis after meals,
where nutrients are absorbed much more slowly? The
answer, although controversial, is likely to be yes. One
thing that supports this idea is that simulating a burst of
insulin at the beginning of a meal in NIDDM normalizes
the postprandial glycemic excursion (92). In other
words, the exaggerated rise in plasma glucose that occurs after meals in NIDDM subjects seems to be due in
part to delayed insulin release.
996
0.500
!<
or
0.400
=> 0.300
0.200
CO
g 0.100
QL
0.000
50
I.L LEAHY
400
120
10080<t
5_ E
300
2 55 60i
a! ^
Acuta
Insulin
40-
Ratponsa
to Arglnina
pU ml
20-
-30
30
60
90
120
-30
30
60
90
200-
120
TIME (MINI
FIG. 4. Plasma insulin response (IRI) to 20-g bolus of intravenous glucose in non-insulin-dependent diabetic
(NIDDM; n = 9 [right]) and nondiabetic control (n = 9
[left]) subjects. Note that 1st phase of insulin response is
totally lacking in NIDDM. Values are means SE. From
Pfeifer et al. (196).
cose concentration, an effect termed glucose potentiation (14,15,82). This process makes teleological sense,
because an unregulated nutrient-based release of insulin
after a period of fasting could cause profound hypoglycemia. Glucose potentiation is studied by administering
a secretagogue at several different glucose levels (attained by short-term glucose infusions). Normally, the
insulin response rises in a linear fashion over a glucose
range of 4.4-25 mM (15; Fig. 6). The PG50 (glucose
value at which the response is 50% of maximum) reflects glucose responsiveness, and the AIRmax (maximum
response) reflects the secretory capacity. In healthy subjects, infused glucose (105), dexamethasone (106), and
experimental insulin resistance (107) all increase the
maximum response, whereas somatostatin lowers it
6Ch
40-
\
20-
0J
r-tHc
-60
0
r-//-
Arginine
10
-60
Minutes
10
Glucose
FIG. 5. Plasma insulin responses (IRI) to intravenous boluses of arginine (2.5 g) and glucose (20 g) in non-insulindependent diabetic (NIDDM; dashed line) and nondiabetic control (solid line) subjects. Note that arginine
causes brisk insulin response in NIDDM, whereas glucose
is without effect. From Palmer et al. (95).
100-
100
200
300
400
500
600
Plasma Glucota-mg/dl
(108). Their effects on PG50 are more variable. The implication is that 3-cells adapt to changing environmental
demands by altering secretory capacity and/or glucose
responsiveness. This mechanism presumably acts as an
important safeguard against hyperglycemia.
In NIDDM, it is predicted that, because of insulin
resistance and hyperglycemia, there should be a marked
increase in secretory capacity. Instead, glucose potentiation is nearly wiped out (14,15,109,110; Fig. 6). It
has been suggested that this defect appears early in the
evolution of NIDDM, perhaps even before the onset of
glucose intolerance (111). The evidence for this statement is that normoglycemic first-degree relatives of patients with type I (insulin-dependent) diabetes,
normoglycemic partially pancreatectomized dogs, and
normoglycemic streptozocin-induced diabetic (STZ-D)
baboons all show the same profound decrease in maximum secretory capacity (112-114). In theory, this loss
means that an inherent (3-cell mechanism that protects
against hyperglycemia is lost early in the course of
NIDDM. Whether this loss actually accelerates the onset
of hyperglycemia is still unknown.
What do we know about the mechanism of the loss?
It is not simply an effect of a lowered (3-cell mass. In its
full-blown form, AIRmax is reduced 90%, whereas the
greatest reduction in (3-cell mass reported to date is only
50% (15,18). Could the inability of glucose to potentiate
and to directly stimulate insulin release be caused by a
single molecular defect, i.e., one that makes the
997
p-cells blind to glucose? A period of improved metabolic control is known to have beneficial effects on
glucose-induced insulin secretion (96-99). An improvement in potentiation would be expected as well,
but this possibility has yet to be tested. The data that do
exist can be construed to either support or deny a single
defect. Phentolamine (115,116) and salicylates
(102,117) improve both the secretory capacity and the
first-phase insulin response. In contrast, the studies
listed above with subclinical [3-cell damage have identified experimental situations where there is a disparity
in the timing of maximum reduction in secretory capacity and maximum reduction in glucose-induced insulin
release (113,114).
Ultradian oscillations of insulin secretion. Like many
hormones, insulin displays a characteristic pulsatile secretory pattern (118). The plasma insulin level oscillates
with a periodicity of 11-13 min (119,120). These oscillations were first described as being in synchrony with
swings in the plasma glucose level and were thus pre-
500
sumed to result from the insulin-glucose negative feedback loop (119). This idea was subsequently questioned
when not all studies could demonstrate a relationship
between glucose and insulin cycles (120,121) and finally discarded when Stagner et al. (122) found the
same type of oscillations in dog pancreases perfused in
vitro with a constant glucose concentration. Our understanding is that they result from an intrinsic p-cell
pacemaker that is under some form of neuronal control
(118). In addition to the oscillations, 10-15 large-amplitude insulin pulses are released each day (4,123).
They occur most prominently (but not exclusively) after
meals, with an ultradian frequency in the range of 1-3
h (Fig. 7). Several kinds of evidence support the concept
that pulsatile release is necessary to maximize insulin
effectiveness (118). First, there is precedence in other
systems that pulsatile release potentiates hormone action (124). Second, insulin pulses are more effective at
inhibiting hepatic glucose production in vitro than is
continuous exposure (125). Furthermore, hepatic glu-
1000
o
E
3
c
o
400
300-
o
0>
CO
=
V)
750
500
200-
c
(J
~
CO
0)
o
250
100
0600
1200
1800
2400
0600
100 -V
0600
1200
1800
2400
0600
B
g
800
E
o
E
3
170-1
11
140-
600
o
110o
0)
CO
400
80-
3
V)
200 H
50-
o
c
CO
a.
o-l
0600
201200
1800
Clock Time
998
2400
0600
0600
1200
1800
2400
Clock Time
0600
J.L. LEAHY
When trying to work through what is known about (3cell dysfunction in NIDDM and how the different defects might contribute to glucose intolerance, a key parameter is to identify when each one begins. Those
found early are candidates for being genetically mediated. In contrast, those acquired after the onset of hyperglycemia may worsen glucose intolerance, but
clearly, they cannot be the initiating lesion. The strategy
used most often is to study people who carry an increased risk of developing NIDDM, e.g., children of
parents with NIDDM, women in remission from gestational diabetes, and certain ethnic groups with high incidence rates. Usually, some kind of measurement is
made in a group of subjects with varying degrees of
glucose tolerance, and the results are stratified according to the ambient glucose level. The idea is twofold:
to identify functional characteristics that are present in
higher frequency and thus might explain the predisposition for NIDDM in this population, and to determine
at what plasma glucose level they first appear. If they
are present in people with only minimal glucose intolerance, the abnormalities are often presumed to be interrelated with the primary genetic etiology. The biggest
shortcoming of this kind of study is its inability to determine whether the changes predate the glucose intolerance or result because of it. A more useful approach,
but one that ends up being a formidable undertaking, is
to follow people as they progress from euglycemia to
overt glucose intolerance. Results from two such studies
are available.
Lillioja et al. (22) studied insulin secretion and sensitivity in 24 Pima Indians as they progressed from normal
to impaired glucose tolerance. The average follow-up
period was 6 yr. When their subjects were euglycemic,
the authors could identify no defects in insulin secretion.
Fasting insulin levels and insulin responses to an oral
glucose challenge were both appropriate for their insulin
sensitivity. Moreover, the first-phase response to intravenous glucose was fully intact. Conversion to impaired
glucose tolerance was associated with a reduction in
insulin sensitivity and appropriate increases in insulin
levels. Again, the first-phase response was more or less
intact.
Warram et al. (133) followed 155 nondiabetic offspring from two NIDDM parents for an average of 13
yr. Twenty-five (16%) went on to develop NIDDM during the study. This subset was more hyperinsulinemic
and insulin resistant at the start of the study (when they
were normally glucose tolerant) than those who remained persistently euglycemic. Also, their first-phase
insulin response at the start of the study was close to
that of a control group, which had no family history of
NIDDM.
Taken together, these results support the notion that
the onset of glucose intolerance in genetically susceptible people cannot be blamed on inadequate insulin
output nor on a reduction in the first-phase insulin response. Both of these defects evolve after glucose intolerance begins. A second conclusion that is often
reached is considerably more controversial. It is stated
that insulin resistance is the earliest finding in these studies and thus must be the primary defect. Other studies
in high-risk ethnic groups (134-137) and relatives of
NIDDM patients (138,139) seem to support this claim.
Collectively, they have found that hyperinsulinemia is
a risk factor for impaired glucose tolerance regardless of
differences in age, weight, and body-fat distribution.
The presumption is that the insulin levels are raised because of insulin resistance and that insulin resistance is
the real risk factor.
The biggest flaw in this reasoning is that insulin resistance is presumed to be of genetic origin. It is just as
likely that a form of |3-cell dysfunction other than a reduction in insulin output could cause the insulin resistance. O'Rahilly et al. (33) were unable to find insulin
pulsations in a group of minimally glucose-intolerant
first-degree relatives of NIDDM subjects, making this
defect a prime candidate. Therefore, despite statements
to the contrary, the jury remains out as to whether pJcell dysfunction, insulin resistance, or a combination of
the two initiate NIDDM.
999
1000
I.L. LEAHY
15
25
35
40
TIME (minutes)
FIG. 8. Insulin secretion in response to glucose and arginine in rats 8-11 wk after 90% pancreatectomy (solidline;
n = 9). Data were obtained with in vitro perfused pancreas
technique. Note that there is brisk response to arginine,
whereas glucose is without effect. In contrast, control rats
(dashed line; n = 7) show clear responses to both secretagogues. From Bonner-Weir et al. (152).
1001
1002
J.L LEAHY
The mechanism of the deleterious effect of hyperglycemia has not been identified. Part of the problem has
been that biochemical studies are classically conducted
in isolated islets, and the profound secretory defects
noted in vivo and in the in vitro perfused pancreas are
no longer present when islets are isolated from diabetic
rats (176-178). We assume that removal of the islets
from the hyperglycemic environment and the time re-
quired for islet isolation together allow glucose responsiveness to recover. Culturing of islets at high glucose
levels also fails to reproduce the defects. There has been
a rash of articles purporting to show glucose desensitization in islets perifused at a high glucose concentration
(179,180). These results were initially quite exciting, but
enthusiasm has been tempered by the recent demonstration that the effect is evanescent (181). Failure to get
glucose unresponsiveness in cultured islets may seem
like evidence against hyperglycemia causing (S-cell dysfunction. However, islets are complex microorgans with
important vascular and cellular relationships that are lost
in a culture system (182). Also, culturing islets is tricky
business, with central necrosis being a common observation. Therefore, the significance of the negative culture data is not at all clear.
There has been a great deal of interest in impaired
glucose transport into the (3-cell explaining the glucose
blindness (145). The concept is a particularly attractive
way to unify the (3-cell dysfunction and insulin resistance in NIDDM. Impaired glucose transport is well established as a key mechanism for the insulin resistance
in peripheral tissues (183,184); a global problem could
then explain the (3-cell defects. Also, several kinds of
data seemed to point in that direction. Insulin secretion
and insulin resistance are both improved by tightened
metabolic control (96-99,185,186). Also, (J-cell dysfunction is unique for glucose.
To address this possibility, we initially measured glucose utilization in isolated islets from our models and
could find no problem (187). However, as stated previously, isolated islets show relatively normal glucoseinduced insulin responses, so that the results were not
definitive. In collaboration with Matschinsky, transport
was assessed in the 90%-pancreatectomy and glucoseinfused models with a novel technique that gets around
the problem of defects reversing. Pancreases were perfused in vitro. After a washout period, glucose was infused for 30 s, and the pancreas was then rapidly removed
and snap frozen. The glucose content of individual islets
was measured with microsurgical and microanalytical
techniques (188). In neither model could we find a decrease in content, thereby essentially ruling out an impairment in transport (189). Based on these results, we
do not believe that 3-cell glucose transport is impaired
or that such a mechanism explains the glucose unresponsiveness.
We are more interested in the opposite concept, that
an abundance of fuel leads to a change in the intracellular microenvironment of the 3-cell, which as an offshoot suppresses glucose responsiveness. The results
obtained in the perfused pancreas with mannoheptulose
and 0 glucose are most easily explained by this idea
(175). Moreover, Sako and Grill (190) have found that
infusion of intralipid, another (3-cell fuel, into normal
rats results in the same kind of 3-cell secretory dysfunction. The nature of the intracellular pathway that is involved remains unknown. Matschinsky's laboratory
(191) has been interested for some time in glucokinase,
1003
SUMMARY
IDDM is characterized both by insulin resistance and p-cell dysfunction. The p-cell abnormalities fall into two distinct types. Early on,
perhaps when glucose tolerance is still normal,
pulsatile insulin delivery is lost. In current understanding, this defect is unrelated to metabolic disruptions attributable to the diabetes. Whether it is acquired or
genetically induced remains a key question. After the
onset of glucose intolerance, a number of other functional abnormalities develop at the same time that pcell glucorecognition is being lost. An important consequence of the glucose blindness is that the inherent
compensatory mechanisms within (B-cells to mitigate
against hyperglycemia are bypassed. This fact is most
clear when the results described in this article are compared to what is known about obesity, another state of
insulin resistance (193). Compensatory increases in (3cell mass (18), quantitative insulin output (194), and
maximum secretory capacity (195) all expand the ability
to protect against hyperglycemia. Also, these changes
occur without any disruption in the pulsatile pattern of
insulin delivery (4). In NIDDM, the combination of hyperglycemia and insulin resistance should be a stronger
stimulus. Instead, (3-cell mass is reduced (18), secretory
capacity is only 10-20% of normal (15), and quantitative insulin output is deficient either in relative or absolute terms, depending on the level of glycemia (9,32).
We have proposed that the glucose unresponsiveness
develops as a direct result of the elevated glucose concentration and have generated substantial data to support this idea in rat models. For instance, normal rats
made hyperglycemic, either by lowering (3-cell mass or
with glucose infusions, develop many of the (3-cell secretory and anatomic features described in NIDDM subjects. A feedforward cycle then exists in which hyperglycemia abolishes the major protective mechanisms
that are in place to guard against hyperglycemia. In theory, a period of improved metabolic control should
break the cycle, and there are a number of short-term
studies showing improvements in both insulin secretion
and insulin resistance (96-99,185,186). Longer-term
data are harder to find, although one study has documented persisting improvements in secretion and sensitivity for 2 wk after cessation of insulin treatment (186).
Therefore, in today's world, the clinical approach to
maximizing endogenous (3-cell function is to aim for the
best metabolic control possible. The measures used
have not changed in 25 years. We still try to lower insulin needs by recommending the things known to increase insulin sensitivity such as physical activity,
1004
ACKNOWLEDGMENTS
REFERENCES
1. Horton ES: Role of environmental factors in the development of noninsulin-dependent diabetes mellitus. Am
} Med75 (Suppl. 1):32-40, 1983
2. Weir GC, Bonner-Weir S, Leahy JL: Islet mass and function in diabetes and transplantation. Diabetes 39:401405, 1990
3. Hellerstrom C, Swenne I, Andersson A: Islet cell replication and diabetes. In The Pathology of the Endocrine
Pancreas in Diabetes. Lefebvre PJ, Pipeleers DG, Eds.
Heidelberg, FRG, Springer-Verlag, 1988, p. 141-70
4. Polonsky KS, Given BD, Van Cauter E: Twenty-four-hour
profiles and pulsatile patterns of insulin secretion in normal and obese subjects. I Clin Invest 81:442-48, 1988
5. Weir GC: Non-insulin-dependent diabetes mellitus: interplay between B-cell inadequacy and insulin resistance. Am } Med 73:461-64, 1982
6. Reaven GM: Insulin secretion and insulin action in noninsulin-dependent diabetes mellitus: which defect is primary? Diabetes Care 7 (Suppl. 1): 17-24, 1984
7. Leahy JL, Weir GC: Noninsulin-dependent diabetes mellitus: current concepts of pathogenesis. In Insulin Secretion: Molecular and Cellular Biology of Diabetes Mellitus. Draznin B, Melmed S, LeRoith D, Eds. New York,
Liss, 1989, p. 149-58
8. Gerich JE: Role of insulin resistance in the pathogenesis
of type 2 (non-insulin-dependent) diabetes mellitus.
Bailliere's Clin Endocrinol Metab 2:307-26, 1988
9. Turner RC, Matthews DR, Clark A, O'Rahilly S, Rudenski AS, Levy J: Pathogenesis of NIDDMa disease of
deficient insulin secretion. Bailliere's Clin Endocrinol
Metab 2:327-42, 1988
10. Kahn SE, Porte D Jr: Islet dysfunction in non-insulindependent diabetes mellitus. Am I Med 85 (Suppl. 5A):
4-8, 1988
11. DeFronzo RA: The triumvirate: (3-cell, muscle, liver: a
collusion responsible for NIDDM. Diabetes 37:667-87,
1988
12. Reaven GM: Role of insulin resistance in human disease.
Diabetes 37:1595-607, 1988
13. Cerasi E, Efendic S, Luft R: Dose-response relation between plasma insulin and blood glucose levels during
oral glucose loads in prediabetic and diabetic subjects.
Lancet 1:794-97, 1973
14. Halter JB, Graf RJ, Porte D Jr: Potentiation of insulin
I.L LEAHY
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
1005
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
1006
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
I.L LLAHY
1167-72, 1987
84. Luzi L, DeFronzo RA: Effect of loss of first-phase insulin
secretion on hepatic glucose production and tissue glucose disposal in humans. Am ) Physiol 257:E241-46,
1989
85. Seltzer HS, Allen EW, Herron ALJr, Brennan MT: Insulin
secretion in response to glycemic stimulus: relation of
delayed initial release to carbohydrate intolerance in
mild diabetes mellitus. ) Clin Invest 46:323-35, 1967
86. Cerasi E, Luft R: The plasma insulin response to glucose
infusion in healthy subjects and in diabetes mellitus.
Acta Endocrinol 55:278-304, 1967
87. Simpson RC, Benedetti A, Grodsky GM, Karam JH, Forsham PH: Early phase of insulin release. Diabetes 17:
684-92, 1968
88. Lerner RL, Porte D Jr: Acute and steady-state insulin
responses to glucose in nonobese diabetic subjects. I
Clin Invest 51:1624-31, 1972
89. Perley MJ, Kipnis DM: Plasma insulin responses to oral
and intravenous glucose: studies in normal and diabetic
subjects. I Clin Invest 46:1954-62, 1967
90. Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, EnsinckJW, Bierman EL, Porte D Jr: Relationships between
fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. / Clin Endocrinol
Metab 42:222-29, 1976
91. Hosker JP, Burnett MA, Matthews DR, Turner RC:
Suppression of insulin secretion by falling plasma glucose levels is impaired in type 2 diabetes. Diabetic Med
5:856-60, 1988
92. Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW:
Physiological importance of deficiency in early prandial
insulin secretion in non-insulin-dependent diabetes. Diabetes 37:736-44, 1988
93. Deckert T: Insulin secretion following administration of
secretin in patients with diabetes mellitus. Acta Endocrinol 59:150-58, 1968
94. Deckert T, Lauridsen UB, Madsen SN, Mogensen P: Insulin responses to glucose, tolbutamide, secretin, and
isoprenaline in maturity-onset diabetes mellitus. Dan
Med Bull 19:222-26, 1972
95. Palmer JP, Benson JW, Walter RM, EnsinckJW: Argininestimulated acute phase of insulin and glucagon secretion
in diabetic subjects. / Clin Invest 58:565-70, 1976
96. Kosaka K, Kuzuya T, Akanuma Y, Hagura R: Increase in
insulin response after treatment of overt maturity-onset
diabetes is independent of the mode of treatment. Diabetologia 18:23-28, 1980
97. Savage PJ, Bennion LJ, Flock EV, Nagulesparan M, Mott
D, Roth J, Unger RH, Bennett PH: Diet-induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes
mellitus. / Clin Endocrinol Metab 48:999-1007, 1979
98. Vague P, Moulin J-P: The defective glucose sensitivity of
the B-cell in noninsulin dependent diabetes: improvement after twenty hours of normoglycemia. Metabolism
31:139-42, 1982
99. Glaser B, Leibovich G, Nesher R, Hartling S, Binder C,
Cerasi E: Improved beta-cell function after intensive insulin treatment in severe non-insulin-dependent diabetes. Acta Endocrinol 118:365-73, 1988
100. Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG: The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus.
Diabetes 34:222-34, 1985
1007
118. Weigle DS: Pulsatile secretion of fuel-regulatory hormones. Diabetes 36:764-75, 1987
119. Lang DA, Matthews DR, Peto J, Turner RC: Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl j Med 301:1023-27,
1979
120. Hansen BC, Jen K-L, Pek SB, Wolfe RA: Rapid oscillations in plasma insulin, glucagon, and glucose in obese
and normal weight humans. ) Clin Endocrinol Metab
54:785-92, 1982
121. Jaspan JB, Lever E, Polonsky KS, Van Cauter E: In vivo
pulsatility of pancreatic islet peptides. Am ) Physiol
251:E215-26, 1986
122. Stagner Jl, Samols E, Weir GC: Sustained oscillations of
insulin, glucagon, and somatostatin from the isolated
canine pancreas during exposure to a constant glucose
concentration. / Clin Invest 65:939-42, 1980
123. Simon C, Brandenberger G, Follenius M: Ultradian oscillations of plasma glucose, insulin, and C-peptide in
man during continuous enteral nutrition. / Clin Endocrinol Metab 64:669-74, 1987
124. Knobil E: The neuroendocrine control of the menstrual
cycle. Recent Prog Horm Res 36:53-88, 1980
125. Komjati M, Bratusch-Marrain P, Waldhausl W: Superior
efficacy of pulsatile versus continuous hormone exposure on hepatic glucose production in vitro. Endocrinology 118:312-19, 1986
126. Goodner CJ, Horn FG, Koerker DJ: Hepatic glucose production oscillates in synchrony with the islet secretory
cycle in fasting rhesis monkeys. Science 215:1257-60,
1982
127. Matthews DR, Naylor BA, Jones RG, Ward GM, Turner
RC: Pulsatile insulin has greater hypoglycemic effect
than continuous delivery. Diabetes 32:617-21, 1983
128. Bratusch-Marrain PR, Komjati M, Waldhausl WK: Efficacy of pulsatile versus continuous insulin administration on hepatic glucose production and glucose
utilization in type I diabetic humans. Diabetes 35:92226, 1986
129. Ward GM, Walters JM, Aitken PM, Best JD, Alford FP:
Effects of prolonged pulsatile hyperinsulinemia in humans: enhancement of insulin sensitivity. Diabetes
39:501-507, 1990
130. Lang DA, Matthews DR, Burnett M, Turner RC: Brief,
irregular oscillations of basal plasma insulin and glucose
concentrations in diabetic man. Diabetes 30:435-39,
1981
131. Matthews DR, Lang DA, Burnett MA, Turner RC: Control of pulsatile insulin secretion in man. Diabetologia
24:231-37, 1983
132. Goodner CJ, Koerker DJ, Weigle DS, McCulloch DK:
Decreased insulin- and glucagon-pulse amplitude accompanying B-cell deficiency induced by streptozocin
in baboons. Diabetes 38:925-31, 1989
133. Warram JH, Martin BC, Gleason RE, Soeldner JS: Slow
glucose removal rate but not insulin secretion predicts
development of NIDDM in offspring of two NIDDM parents (Abstract). Diabetes 36 (Suppl. 1):14A, 1987
134. Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson
JK: Hyperinsulinemia in a population at high risk for
non-insulin-dependent diabetes mellitus. N Engl I Med
315:220-24, 1986
135. Haffner SM, Stern MP, Mitchell BD, Hazuda HP, Patterson JK: Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels,
1008
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
J.L LEAHY
152. Bonner-Weir S, Trent DF, Weir GC: Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release, j Clin Invest 71:1544-53, 1983
153. Penhos JC, Wu C-H, Basabe JC, Lopez N, Wolff FW: A
rat pancreas-small gut preparation for the study of intestinal factor(s) and insulin release. Diabetes 18:733
38, 1969
154. WeirGC, Knowlton SD, Martin DB: Glucagon secretion
from the perfused rat pancreas: studies with glucose and
catecholamines. J Clin Invest 54:1403-12, 1974
155. WeirGC, Clore ET, Zmachinski CJ, Bonner-Weir S: Islet
secretion in a new experimental model for non-insulindependent diabetes. Diabetes 30:590-95, 1981
156. Trent DF, Fletcher DJ, May JM, Bonner-Weir S, Weir GC:
Abnormal islet and adipocyte function in young B-celldeficient rats with near-normoglycemia. Diabetes
33:170-75, 1984
157. Leahy JL, Bonner-Weir S, Weir GC: Abnormal glucose
regulation of insulin secretion in models of reduced Bcell mass. Diabetes 33:667-73, 1984
158. Giroix M-H, Portha B, Kergoat M, Bailbe D, Picon L:
Glucose insensitivity and amino-acid hypersensitivity of
insulin release in rats with non-insulin-dependent diabetes: a study with the perfused pancreas. Diabetes
32:445-51, 1983
159. Portha B, Blondel O, Serradas P, McEvoy R, Giroix M-H,
Kergoat M, Bailbe D: The rat models of non-insulin dependent diabetes induced by neonatal streptozotocin. Diabete Metab 15:61-75, 1989
160. Grill V, Rundfeldt M: Abnormalities of insulin responses
after ambient and previous exposure to glucose in streptozocin-diabetic and dexamethasone-treated rats: role of
hyperglycemia and increased B-cell demands. Diabetes
35:44-51, 1986
161. Leahy JL, Weir GC: Unresponsiveness to glucose in a
streptozocin model of diabetes: inappropriate insulin
and glucagon responses to a reduction of glucose concentration. Diabetes 34:653-59, 1985
162. Leahy JL, Halban PA, Weir GC: Increased pancreatic
proinsulin: insulin ratio in diabetic rats (Abstract). Diabetes 38 (Suppl. 2):206A, 1989
163. Leahy JL, Halban PA, Weir GC: Enhanced proinsulin
secretion in diabetic rats is not explained by abnormal
processing (Abstract). Diabetes 39 (Suppl. 1):137A,
1990
164. Leahy JL, Cooper HE, Deal DA, Weir GC: Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion: a study in normal rats using
chronic in vivo glucose infusions.) Clin Invest 77:90815, 1986
165. Leahy JL, Bonner-Weir S, Weir GC: Abnormal insulin
secretion in a streptozocin model of diabetes: effects of
insulin treatment. Diabetes 34:660-66, 1985
166. Kergoat M, Bailbe D, Portha B: Insulin treatment improves glucose-induced insulin release in rats with
NIDDM induced by streptozocin. Diabetes 36:971-77,
1987
167. Voyles NR, Powell AM, Timmers Kl, Wilkins SD, Bhathena SJ, Hansen C, Michaelis OE, Recant L: Reversible
impairment of glucose-induced insulin secretion in SHR/
N-cp rats: genetic model of type II diabetes. Diabetes
37:398-404, 1988
168. Brockenbrough JS, Weir GC, Bonner-Weir S: Discordance of exocrine and endocrine growth after 90% pancreatectomy in rats. Diabetes 37:232-36, 1988
169. Bonner-Weir S, Deery D, Weir GC: Growth of regenerating islet tissue is enhanced by VMH lesions (Abstract). Diabetes 35 (Suppl. 1):97A, 1986
170. Leahy JL, Cooper HE, Weir GC: Impaired insulin secretion associated with near normoglycemia: study in normal rats with 96-h in vivo glucose infusions. Diabetes
36:459-64, 1987
171. Leahy JL, Weir GC: Evolution of abnormal insulin secretory responses during 48-h in vivo hyperglycemia.
Diabetes 37:217-22, 1988
172. Leahy JL, Bonner-Weir S, Weir GC: Rapid reversal of Bcell defects caused by chronic hyperglycemia (Abstract).
Diabetes 37 (Suppl. 1):6A, 1988
173. Starke A, Grundy S, McGarry JD, Unger RH: Correction
of hyperglycemia with phloridzin restores the glucagon
response to glucose in insulin-deficient dogs: implications for human diabetes. Proc Natl Acad Sci USA
82:1544-46, 1985
174. Rossetti L, Shulman Gl, Zawalich W, DeFronzo RA: Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. / Clin Invest
80:1037-44, 1987
175. Grill V, Westberg M, Ostenson C-G: B cell insensitivity
in a rat model of non-insulin-dependent diabetes: evidence for a rapidly reversible effect of previous hyperglycemia. / Clin Invest 80:664-69, 1987
176. Halban PA, Bonner-Weir S, Weir GC: Elevated proinsulin biosynthesis in vitro from a rat model of non-insulin-dependent diabetes mellitus. Diabetes 32:277-83,
1983
177. Portha B: Decreased glucose-induced insulin release
and biosynthesis by islets of rats with non-insulin-dependent diabetes: effect of tissue culture. Endocrinology
117:1735-41, 1985
178. Portha B, Giroix M-H, Serradas P, Welsh N, Hellerstrom
C, Sener A, Malaisse WJ: Insulin production and glucose
metabolism in isolated pancreatic islets of rats with
NIDDM. Diabetes 37:1226-33, 1988
179. Bolaffi JL, Heldt A, Lewis LD, Grodsky GM: The third
phase of in vitro insulin secretion: evidence for glucose
insensitivity. Diabetes 35:370-73, 1986
180. Grodsky GM: A new phase of insulin secretion: how
will it contribute to our understanding of p-cell function?
Diabetes 38:673-78, 1989
181. Giroix M-H, Serradas P, Portha B: The desensitization
of normal B-cells to glucose in vitro is transient and not
related to high glucose levels. Endocrinology 125:19992007, 1989
182. Weir GC, Bonner-Weir S: Islets of Langerhans: the puzzle of intraislet interactions and their relevance to diabetes. } Clin Invest 85:983-87, 1990
183. Ciaraldi TP, Kolterman OG, Scarlett JA, Kao M, Olefsky
JM: Role of glucose transport in the postreceptor defect
of non-insulin-dependent diabetes mellitus. Diabetes
31:1016-22, 1982
184. Garvey WT, Kolterman OG: Correlation of in vivo and
in vitro actions of insulin in obesity and noninsulin-dependent diabetes mellitus: role of the glucose transport
system. Diabetes Metab Rev 4:543-69, 1988
185. Scarlett JA, Gray RS, Griffin J, Olefsky JM, Kolterman
OG: Insulin treatment reverses the insulin resistance of
type II diabetes mellitus. Diabetes Care 5:353-63, 1982
186. Andrews WJ, Vasquez B, Nagulesparan M, Klimes I,
FoleyJ, Unger R, Reaven GM: Insulin therapy in obese,
non-insulin-dependent diabetes induces imorovements
1009
187.
188.
189.
190.
191.
1010
13, 1984
192. Malaisse WJ: Possible sites for deficient glucose recognition in islet cells. In The Pathology of the Endocrine
Pancreas in Diabetes. Lefebvre PJ, Pipeleers DG,
Eds. Heidelberg, FRG, Springer-Verlag, 1988, p. 219
32
193. Kolterman OG, Insel J, Saekow M, Olefsky JM: Mechanisms of insulin resistance in human obesity: evidence
for receptor and postreceptor defects. ) Clin Invest
65:1272-84, 1980
194. Polonsky KS, Given BD, Hirsch L, Shapiro ET, Tillit H,
BeebeC, Galloway JA, Frank BH, KarrisonT, Van Cauter
E: Quantitative study of insulin secretion and clearance
in normal and obese subjects. J Clin Invest 81:435-41,
1988
195. Beard JC, Ward WK, Halter JB, Wallum BJ, Porte D Jr:
Relationship of islet function to insulin action in human
obesity. J Clin Endocrinol Metab 65:59-64, 1987
196. Pfeifer MA, Halter JB, Porte D Jr: Insulin secretion in
diabetes mellitus. Am } Med 70:579-88, 1981