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John L.

Leahy, MD

Natural History of P-Cell

Dysfunction in NIDDM

Non-insulin-dependent diabetes mellitus (NIDDM)

is characterized by insulin resistance and p-cell
dysfunction. This review focuses on the p-cell, what
defects occur when and why. Two major anatomic
observations have been made in NIDDM. The p-cell
mass is mildly reduced, especially when obesity is taken
into account. Also, amyloid deposits are frequently
observed in the islets. It is unclear whether these
changes are genetically mediated or result secondary
to the loss of glucose homeostasis. Many studies have
looked at some aspect of insulin secretion in NIDDM,
and two types of distinct abnormalities have been
described. Early on, there is a marked disruption in
pulsatile insulin delivery, which is potentially an
important contributor to the insulin resistance. It is
unclear whether the loss of pulsatile delivery is acquired
or genetically induced. Later, after glucose intolerance
has started, several other secretory abnormalities
develop coincident with loss of p-cell glucorecognition.
The net result is further deterioration in timing of
insulin delivery and postprandial hyperglycemia. A
second important consequence of the glucose blindness
is that the inherent compensatory p-cell mechanisms
that guard against hyperglycemia are bypassed. We
propose that the loss of glucose responsiveness is a
direct result of an elevated glucose concentration (socalled glucotoxicity) and have generated substantial
data in rat models that support this idea. The logical
conclusion is that P-cell function in NIDDM can be
maximized by achieving the best metabolic control
possible. Diabetes Care 13:992-1010, 1990

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.


n simplest terms, glucose tolerance is normal when

insulin secretion and insulin needs perfectly balance. The relationship is a dynamic one; numerous
environmental and physiological influences at various stages of life make us less insulin sensitive (1). The
fact that only a small percentage of people become diabetic as they grow older, less active, and fatter attests
to the system's ability to compensate. The regulatory
component is the endocrine pancreas working through
a classic negative feedback loop; a rising plasma glucose level stimulates insulin secretion and, over a longer
period, promotes growth of more p-cells (2,3). Indeed,
as the complicated fluctuations in insulin release that
occur throughout the day are better appreciated, the
preciseness of the system is marvelous (4).
Non-insulin-dependent diabetes mellitus (NIDDM) is
characterized by glucose intolerance, and the debate
has raged for more than two decades whether insulinsecretory dysfunction or insulin resistance is the cause
(5,6). Current understanding is that NIDDM is a genetic
disorder, probably of a heterogenous nature, and that
insulin secretion and insulin sensitivity both must be
defective to get full phenotypic expression (7). No convincing data have yet proved whether one type of defect
predates the other, and it remains to be determined
whether both are genetically mediated or one causes
the other. The ideal approach would be to take individuals who have inherited the NIDDM gene(s) and to
study them years before the onset of glucose intolerance. However, the lack of genetic or functional markers effectively precludes this strategy. Several groups
have instead used people at increased risk for NIDDM,
e.g., children of parents with NIDDM, women in remission from gestational diabetes, and certain ethnic
populations with high incidence rates. These studies
have not settled the "which comes first" dilemma. They



have, however, contributed to the understanding of the

natural history of p-cell dysfunction and insulin resistance by providing glimpses of abnormalities in euglycemic individuals.
This review focuses on (3-cell function in NIDDM,
what defects occur and when, their possible causes, and
what implications they may hold for treatment and prevention of the disease. This article is not a comprehensive discussion of the pathogenesis of NIDDM: readers
wanting to learn more about the controversy between
(3-cell dysfunction and insulin resistance are referred to
reviews from some of the leading investigators in the
field (8-12).


Many studies have examined some aspect of insulin secretion in NIDDM. Usually, fasting insulin values or
stimulated responses are compared directly with those
of nondiabetic control subjects. This approach is not
unreasonable when the aim is to determine, under basal
conditions, whether tissues are exposed to subnormal
concentrations of insulin. Studies that try to prove or
disprove that (3-cell function is normal are faced with a
much more difficult challenge. The complex nature of
p-cell secretory responses makes it nearly impossible to
control for all of the variables that affect insulin output.
Some of the better-known examples follow.
Ambient plasma glucose concentration. The insulinotropic effect of most secretagogues varies with the
plasma glucose concentration. Increasing the glucose
level in healthy subjects from basal to 10 mM causes
insulin responses to standardized challenges to rise as
much as 5-to 10-fold (13-15). It follows that studies on
NIDDM and nondiabetic control subjects should be
conducted at the same glucose value. Some authors
have even argued that matching glucose values is not
enough but that responses should be mapped out over
a wide range of glycemia (16).
Mass of functional p-cells. The quantity of p-cells determines how much insulin is released to a particular
stimulus (17). Although there is some disagreement,
studies that used modern techniques generally found
that the (3-cell mass in NIDDM is reduced (18,19). Reversal studies where insulin responses are compared before and after treatment routinely underestimate benefits
by failing to consider the smaller |3-cell mass.
Degree of insulin resistance. Plasma insulin levels
(fasting and stimulated responses to standardized challenges) vary in an inverse fashion with insulin sensitivity
(20-23). In other words, insensitive people put out
more insulin than sensitive individuals to the same stimulus. To negate this effect, insulin-secretion studies in
nondiabetic subjects are routinely performed in age- and
weight-matched subjects. The practice has carried over
to studies between NIDDM and nondiabetic control
subjects, which defeats the original purpose because of
the diabetes-associated insulin resistance (11).


Factors that preclude direct comparison of plasma

insulin values in diabetic and nondiabetic subjects.
The last few years have seen the emergence of techniques to directly measure the insulin secretion rate in
humans (24-26). Few studies have used this technology, so that much current knowledge is based on the
assumption that plasma insulin levels (basal and stimulated responses) are reasonable indicators of insulin
output. The presumption is that two people with the
same values have the same output, whereas a difference
indicates dissimilar output. Recently, several factors
have been identified that raise serious doubts about the
validity of directly comparing insulin values in diabetic
and nondiabetic subjects. First, after being released into
the portal vein, 50% of secreted insulin is degraded during its first pass through the liver (27). It has been suggested, based on insulin-C-peptide ratios, that a smaller
percentage is lost in NIDDM (28,29). Second, all insulin
assays cross-react to some degree with proinsulin.
Therefore, insulin measurements are a mixture of insulin
and its inactive precursor (30). In NIDDM, proinsulin is
present in unusually large amounts, artifactually raising
insulin values (31,32). Finally, insulin is released as a
complicated series of oscillations and postprandial
spikes (4). In NIDDM, this pulsatility is profoundly disrupted (33,34), but there is no indication of this fact in
either fasting or stimulated plasma insulin values. Both
are indistinguishable from those of nondiabetic control
subjects (34).
In summary, we have learned a great deal about insulin secretion in NIDDM without having taken into account the factors listed above. They are most important
when trying to interpret quantitative insulin output.
Missing responses and aberrant patterns of release are
still identifiable. In contrast, the literature is replete with
statements about normal versus abnormal (3-cell function based on quantitative data when many or all of the
relevant variables have been ignored. When viewing
these data, readers should use caution and follow the
dictum that appropriate insulin secretion will continue
to be a difficult concept until all of the factors that affect
the secretion rate are defined and routinely controlled.


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-



pared to the control subjects closest in age. The study

by Kloppel et al. (18) is particularly noteworthy, not
only because it is one of the largest, but because it controlled for the presence of obesity. The major findings
are shown in Table 1. In control subjects, obesity caused
a doubling of @-cell mass, which points out how important weight matching is in this kind of study. Furthermore, both groups of diabetic subjects had clearly
reduced |3-cell masses. The only dissenting article found
complete overlap between 8 NIDDM patients and 8
age-matched control subjects (38). Of interest, most
other studies have used patients with long-standing diabetes, and 4 of their patients were of recent onset. Also,
no indication is given about how the groups matched
for obesity.
The finding of a modestly reduced (3-cell mass is made
even more impressive by the understanding that insulin
resistance, unassociated with glucose intolerance from
obesity, Cushing's disease, and acromegaly (18,39,40),
and sustained hyperglycemia (3,41,42) are both potent
stimulants for compensatory p-cell growth. Taken together, the (3-cell mass in NIDDM is clearly far below
what would be expected given the metabolic demands.
Is the decrease specific for (3-cells? The data concerning
the other islet cells (non-P-cells) are not definitive: normal (19,37,38) and reduced (18,36) non-p-cell masses
have both been reported.
Morphologically, the islets appear normal. Insulitis is
never present (43). Also missing is evidence for the hyperactivity that might be expected in response to hyperglycemia: few mitotic figures are found (3,18,43),
and overt (3-cell degranulation is unusual (44). An exciting recent development concerns amylin or islet amyloid polypeptide, the protein that makes up the amyloid
deposits that appear frequently in the islets of people
with NIDDM (45-47). Amyloid infiltration was first associated with diabetes about 90 years ago (48). Until
recently, it was thought to hold no particular significance. One reason for the lack of interest was that amyloid deposits were occasionally found in nondiabetic
elderly people (49).
Amylin has been cloned (50,51) and its biochemistry
and molecular biology studied (45-47). It is a 37-amino
acid protein that is produced normally by the (3-cell,
copackaged with insulin in secretory granules (52), and
cosecreted into the sinusoidal space (53). For unclear
reasons, in NIDDM, this material tends to accumulate

extracellularly in close contact with (3-cells and to form

fibrils (54). There is increasing interest that these fibrils
could lower functional p-cell mass either by plugging
up the sensing and/or secreting areas of the cell or
through direct cellular breakdown (45,46). The best evidence supporting a role for amylin has been obtained
in spontaneously diabetic monkeys, where the appearance of amyloid directly precedes glucose intolerance
and its extent correlates with the severity of diabetes
Recently, the amylin story has taken an unexpected
twist. In pharmacologic amounts, amylin has been reported to lower basal and insulin-stimulated glycogen
synthetase in muscle (56,57) and to inhibit glucose-stimulated insulin secretion from isolated rat islets (58).
These abnormalities are the same ones acknowledged
to be the key insulin-secretion and insulin-resistance defects in NIDDM. The question yet to be answered is
whether physiological concentrations produce the same
In summary, the major anatomical findings are a reduced p-cell mass and the occurrence of amyloid deposits. The key question is to determine when these
changes occur: Do they predate the onset of glucose
intolerance? Could a genetic defect that prevents (3-cell
mass from being maintained above a critical level, or
one that causes amyloid to accumulate, be a candidate
for what causes the susceptibility to hyperglycemia? In
humans, there is a dearth of information on (3-cell mass
and amyloid infiltration in prediabetes. Alternatively,
could these observations be secondary to glucose intolerance? In animals, it has been reported that long-term
severe hyperglycemia has a cytotoxic effect on (3-cells,
but the relevance of this observation to NIDDM is unclear (59,60).


Several distinct defects in insulin secretion have been
identified in NIDDM. This section describes each in detail and how they might contribute to glucose intolerance. A later section covers the time of onset.
Fasting and 24-h plasma insulin values. Thirty years
ago, Yalow and Berson (61) showed that NIDDM could
not be blamed simply on inadequate insulin delivery.
They found, with their newly developed radioimmu-

Pancreatic morphometry in obese and nonobese NIDDM and control subjects

(3-Cell volume (ml)

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.




noassay, that insulin levels in maturity-onset patients

were at least the equal of control subjects. That study
was not matched for degree of obesity, but DeFronzo
(11) has reviewed 32 others performed in nonobese subjects, and in none were insulin levels subnormal. Several investigators have expanded on this observation,
showing that there is a definable pattern to the fasting
insulin level, the so-called inverted-U-shaped curve
(62-64; Fig. 1). Early on, insulin values are slightly increased. With worsening glycemia, they rise, peak at a
glucose value of 7.8 mM, and thereafter fall back to the
control range. Even in the face of marked hyperglycemia, overt hypoinsulinemia is rare (65). Insulin profiles (multiple samples collected throughout the day)
have shown the same results. Severely hyperglycemic
subjects, especially those who are obese, tend to have
delayed and decreased postprandial responses, but lesshyperglycemic subjects maintain insulin levels in the
normal range (66-68) throughout the day.
Based on these results, the prevailing opinion is that
NIDDM is never characterized by hypoinsulinemia and
that, early on, patients are frankly hyperinsulinemic. This
widely held belief needs rethinking because of recent
changes in our understanding of insulin measurements.
All of these studies were conducted with insulin radioimmunoassays that cross-react not only with insulin
but also with insulin precursors, the best known being
proinsulin. The amount of proinsulin secreted compared
with insulin is trivial (69). Its clearance rate, however,
is considerably slower, so that proinsulin comprises 1525% of a normal insulin value (32,70,71). Studies in the
1970s that used chromatographic techniques showed
that proinsulin made up an even larger fraction in
NIDDM (72-74), and this observation has been con-






5 -




180 220 260


Fasting Plasma Glucose (mg/dl)

FIG. 1. Fasting immunoreactive plasma insulin levels in
nonobese subjects stratified by level of glycemia. From
DeFronzo et al. (63).


firmed by several laboratories with specific proinsulin

assays (32,71,75-78). There is remarkable agreement
among these different studies: when insulin values are
adjusted for the proinsulin concentration, subjects with
moderate to severe hyperglycemia (fasting glucose value
>10 mM) have true insulin levels that tend to be or are
frankly below those of weight-matched control subjects.
In other words, excessive amounts of proinsulin have
masked the subnormal insulin levels.
Important questions raised by these results are: When
does the relative increase in circulating proinsulin occur? Are people with mild fasting hyperglycemia truly
hyperinsulinemic? Does the inverted-U-shaped curve
reflect increasing insulin or proinsulin levels (Fig. 1)?
The data generated under fasting conditions are too limited for a definite conclusion. In contrast, insulin responses to oral glucose challenges show the same
inverted-U-shaped curve (62), and a recent study has
quantified proinsulin and true insulin responses over a
wide range of glycemia (76). The inverted U clearly
results because of changing insulin output (Fig. 2).
Proinsulin rises during the same period, but its contribution to overall immunoreactivity is rather minor. Figure 2 also reinforces the claim that insulin responses in
moderate and severe hyperglycemia are subnormal. The
ratio of proinsulin to insulin from the same data is plotted on Fig. 3. The curve rises sharply and plateaus at a
value nearly four times that of the control subjects, and
it is not difficult to see how proinsulin has confused the
interpretation of insulin values. Moreover, Fig. 2 actually minimizes the proinsulin contribution to overall
immunoreactivity because the data are expressed in molarity. Insulin values have traditionally been expressed
in units based on weight (|xU/ml). Proinsulin weighs
50% more than insulin, so in that situation, its contribution is even greater.
Therefore, under basal conditions, circulating insulin
values can be summarized as follows: /) nonobese subjects with impaired glucose tolerance are hyperinsulinemic versus age- and weight-matched control subjects, 2) mildly hyperglycemic subjects (fasting glucose
values 7.2-10.0 mM) have fasting and stimulated insulin values equal to those of control subjects, and 3)
more severely hyperglycemic subjects are overtly hypoinsulinemic. It must be reemphasized that these results do not mean that insulin values are normal in
patients with mild hyperglycemia, just that they are no
different than those in control subjects. Normal insulin
values in the face of any degree of hyperglycemia are
inappropriate (79).
Stimulated insulin responses to standardized challenges. The main regulator of insulin secretion is the
plasma glucose level (80). Raising it above 5.5 mM elicits a biphasic insulin response, the first phase lasting 5
10 min and the second phase persisting for the duration
of hyperglycemia (81,82). The first phase serves an important physiological function. It mediates efficient
clearance of a glucose load, which is demonstrated most
clearly by the observation that experimentally suppress-





2000 g


1600 5

o 1200

1200 F























FIG. 2. Integrated true insulin () and proinsulin () responses to 100-g oral glucose challenge stratified by level
of glycemia. From Yoshioka et al. (76).

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.


There is a long list of agents other than glucose that

stimulate insulin secretion. As a group, NIDDM patients
elicit relatively normal-looking insulin responses that are
not delayed (82,87,93-95; Fig. 5). Therefore, glucose's
inability to elicit the early burst of insulin cannot be
blamed on some fundamental problem within the pcell. Instead, the secretory defect is specific for glucose,
and it is commonly referred to as selective glucose unresponsiveness.
An area of active research during the last decade has
been to try to establish why p-cells become refractory
to glucose. Several (96-99) but not all (100) studies
have shown partial return of the first phase after a period
of tight metabolic control. This last study (100) failed to
show improvement after 3 wk of continuous subcutaneous insulin infusion. However, the plasma glucose
values during testing averaged 8.6 mM, which may explain the negative findings. Therefore, the concept is
that a metabolic derangement linked in some way to
the diabetes causes the p-cells to become glucose unresponsive. Our laboratory has pursued the hypothesis
that the hyperglycemia itself is the toxic agent. It has
also been observed that naloxone (101) and inhibitors
of prostaglandin E2, e.g., salicylates (102), improve firstphase release, and a second area of investigation concerns endogenous substances such as opioids and prostaglandins (103,104).
Glucose potentiation of insulin secretagogues. In essentially all nonglucose secretagogues, the magnitude
of their insulin responses depends on the ambient glu-




=> 0.300

g 0.100


100 150 200 250 300


FIG. 3. Proinsulin-insulin ratio calculated from integrated
responses generated by 100-g oral glucose challenge. Results are stratified by level of glycemia. From Yoshioka et
al. (76).





5_ E


2 55 60i
a! ^



to Arglnina
pU ml














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












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).









Plasma Glucota-mg/dl

FIG. 6. Acute insulin responses to 5 g arginine i.v. at 5

matched glucose levels in non-insulin-dependent diabetic
(NIDDM; O; n = 8) and nondiabetic control (; n = 8)
subjects. Note that maximum response is markedly attenuated in NIDDM. From Ward et al. (15).

(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



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-


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-

















100 -V















200 H






Clock Time








Clock Time


FIG. 7. Patterns of insulin secretion

over 24 h in non-insulin-dependent diabetic (NIDDM) and nondiabetic control
subjects. Two representative profiles
from NIDDM (C and D) and control (A
and B) subjects are included. Note in
control subjects how pulses after meals
progressively fall in amplitude. In contrast, number of spikes in NIDDM remains relatively normal, but their
amplitude is smaller, and pattern of progressive postprandial fall is no longer
present. From Polonsky et al. (34).



cose production in vivo oscillates in an inverse fashion

perfectly in synchrony with insulin pulses (126). Finally,
pulsed insulin has a greater hypoglycemic effect than
continuously infused insulin (127-129). It can be concluded that the pulsatility is not an accident of nature.
Instead, the precisely coordinated pattern is a key component of the glucoregulatory system.
It is interesting then that NIDDM subjects no longer
have the normal pattern of insulin delivery. Rapid oscillations are gone (130,131). Also, the number of postprandial pulses is the same, but their size and temporal
organization are markedly different (34; Fig. 7). It has
yet to be proved that nonpulsatile release has negative
physiological consequences. However, it is an attractive
possibility that not having the pulsatile pattern of insulin
delivery either contributes to or may even cause the
insulin resistance in NIDDM. Supporting this later suggestion, it has been reported that minimally glucoseintolerant first-degree relatives of probands with NIDDM
are without insulin oscillations (33), nor are they found
in NIDDM subjects who attain euglycemia with diet
therapy (130). Finally, in STZ-D baboons, whose fasting
glucose goes from 4.6 to 5.8 mM, the pattern of insulin
pulses is still intact (132). These results strongly support
the idea that the disrupted pattern of insulin release predates the glucose intolerance. Also, there does not appear to be any direct relationship between the loss of
pulsatility and glucose intolerance. A high priority for
the future should be to unravel what role the disorganized pattern of insulin release plays in the pathophysiology of NIDDM.


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
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
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.




When the results detailed above are viewed together,
we can start to put together a profile of what happens
to insulin secretion during the evolution of NIDDM. It
remains speculative whether there is a genetic lesion
directed at the (3-cell and what the nature of it could
be. It has been known for well over a decade that,
among normoglycemic individuals, low insulin responders are the ones most prone to develop NIDDM
(16,140,141). Not much is known about how secretory
capacity is regulated. One factor is fJ-cell mass, and low
insulin responders could simply be at the lower end of
the curve. Alternatively, a gene mutation could lower
the actual or functional (3-cell mass through early senescence or amyloid accumulation. A second factor is
quantitative insulin output independent of (3-cell mass.
It is not known whether genetics plays any part in its
regulation. Another kind of possibility, which has previously been discussed, concerns genetically mediated
alterations in the pattern and timing of insulin release.
Progression from normal to impaired glucose tolerance is accompanied by rising basal and postprandial
insulin levels, which presumably reflect worsening hyperglycemia and insulin resistance. Quantitative insulin
output seems to be appropriate for the metabolic conditions, but the timing of delivery is totally off (22,33).
There are too few data to know exactly when glucose
potentiation is lost, but that may also occur at this early
stage. Therefore, the characteristic p-cell defect is nonpulsatility of insulin delivery. Key areas of investigation
for the future are to determine whether the nonpulsatile
pattern is genetically mediated or acquired and to unravel how the defect in timing interrelates with the insulin resistance.
As the individual progresses to measurable glucose
intolerance (impaired glucose intolerance), overall insulin output continues to rise and peaks at a plasma
glucose level of 7.8 mM (22). p-Cells now become refractory to glucose, which results in further deterioration
in the timing of insulin delivery (90). The net effect is
to worsen postprandial hyperglycemia. Therefore, this
stage is characterized by the onset of selective glucose
The risk to progress from impaired glucose tolerance
to overt NIDDM is in part based on the (3-celI's capacity
to rise to the challenge. Kadowaki et al. (142) followed
288 Japanese subjects with impaired glucose tolerance
for 8 yr. Forty-eight progressed to overt NIDDM. When
they went back and reexamined the data from the beginning of the study, they found that the subgroup with
the lowest insulin responses during an oral glucose challenge were the ones who developed NIDDM. The identical observation has been made by other investigators
(136,143). This observation is perfectly consistent with
those made in nondiabetic subjects showing that low
insulin responders are the group at highest risk for
NIDDM (16,140,141).


As overt NIDDM sets in, insulin output falls off, and

by the time the fasting glucose value is 10 mM the insulin concentration is frankly subnormal. It is not clear
what the relationship is between these two. Higher glucose values could cause insulin output to fall because
of glucotoxicity. Alternatively, insulin output could fall
due to reductions in (3-cell mass and/or secretory capacity and worsen hyperglycemia on that basis. Therefore, this stage is characterized by the shift from relative
to absolute insulin deficiency. Glucose unresponsiveness, absolute insulin deficiency, and nonpulsatile insulin delivery are now all present, so that the picture of
P-cell secretory dysfunction is complete.


The fundamental purpose of fJ-cells is to keep the
plasma glucose concentration in a relatively narrow
range. It can be inferred that deviations either above or
below are undesirable and might have major consequences. The danger of an abnormally low glucose level
is obvious. Moreover, there is a growing literature that
prolonged elevations cause a number of cell types to
dysfunction. In NIDDM, plasma glucose stays above the
normal range- When the pathophysiology of this observation was investigated, it was found that the (3-cells
had effectively become refractory to glucose. Understanding that fact then ties together most of what has
been described in this article about (3-cell mass/morphology and insulin secretion. Loss of glucose-stimulated insulin release and glucose potentiation are
obvious examples. The anatomic findings are also consistent. A reduced p-cell mass, lack of evidence for
accelerated (3-cell growth, and relatively normal granulation are all contrary to what would be expected given
the high glucose environment (3,43). As such, a major
problem that stems from the p-cell's inability to recognize glucose is that the hyperglycemia-induced compensatory changes in p-cell mass and function that
should occur do not. Therefore, glucose unresponsiveness is rightfully considered to be a major (3-cell defect,
and there has been intense interest over the last decade
to define its cause.
A guiding principle has been the appreciation that
whatever mechanism is finally decided on must be able
to explain all of the experimental observations. Three of
the most important ones are 7) the biphasic pattern of
insulin release is intact in nondiabetic individuals destined to become glucose intolerant (22,133), 2) the first
phase is lost during the time that the fasting glucose level
goes from 5.5 to 6.4 mM (90), and 3) tight metabolic
control partially restores the first phase (96-99). Therefore, the underlying defect must result in part because
of some metabolic change induced by the diabetes, and
that change must occur after the glucose intolerance has
started but when it is still rather mild. Our group has
pursued the hypothesis that the rising glucose level itself



makes the fi-cells unresponsive to glucose, a process

recently termed glucotoxicity.
The suggestion that hyperglycemia induces changes
in fJ-cell function is not a new one (5,144,145). Classic
studies in the 1940s showed that glucose injections in
partially pancreatectomized cats caused permanent diabetes (146). A recent study has reproduced the same
results with glucose infusions in partially pancreatectomized dogs (60). There are also data in humans that
are consistent with a link between hyperglycemia and
glucose unresponsiveness. Dimitriadis etal. (147) found
that healthy subjects made hyperglycemic for 12 h failed
to suppress insulin output during hypoglycemia. Studies
in humans are faced with a number of limitations, not
the least of which is the inability to make healthy subjects hyperglycemic for any significant period of time
(148,149). Thus, we have performed our studies in rat
models, and have generated a large amount of data that
support the concept of hyperglycemia-induced (3-cell
dysfunction. Our work has been described in two comprehensive reviews (41,150). As such, I will only highlight the major findings and our current thoughts.

Reduced p-cell mass. The first step was to determine

whether inducing hyperglycemia in normal rats, by lowering their (3-cell mass, would alter the remaining pcells. Rats were given STZ in the neonatal period (151)
or underwent a 90% pancreatectomy at 5 wk of age
(152). Both models are characterized by modest nonfasting hyperglycemia and, germane to this discussion,
p-cell masses that average 4 0 - 5 0 % of normal
(151,152). Insulin-secretion studies were conducted in
vitro with an organ perfusion system (153,154). This
technique allows the operator to map out secretory responses on a minute-to-minute basis under precisely defined conditions. The results obtained for both models
were similar. Glucose failed to stimulate insulin release
(152,155,156). In contrast, nonglucose responses were
present and at times were abnormally large
(152,155,157). Therefore, the remaining (3-celIs
showed the pattern of selective glucose unresponsiveness (Fig. 8). Similar results have been reported by other
laboratories (158-160).
We went on to study other aspects of P-cell function
and obtained results that were reminiscent of human
NIDDM. Insulin output failed to suppress when the glucose concentration was lowered (161). The relative proportion of proinsulin in pancreas extracts and portal vein
samples was increased (162,163). Glucose potentiation
was essentially wiped out (157). This last result needs
further comment. The 90%-pancreatectomized rats
showed a potentiation pattern that was like what has
been described in NIDDM subjects, i.e., a marked decrease in maximum secretory capacity (15,157). In contrast, the neonatal STZ model had near-maximum
responses at both low and high glucose concentrations
(157). In other words, the STZ-D rats failed to suppress
insulin responses at a low glucose concentration, and






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).

the pancreatectomy model failed to augment them at a

high glucose level. The pattern in the STZ-D rats ended
up being an important milestone in our studies. The
pattern resembled what would be expected from hyperglycemia, the (3-cells seeming to behave as if the
glucose level was high even when it really was not, and
we were able to establish a direct link between the two
by reproducing the pattern in normal rats with glucose
infusions (164). The connection is further strengthened
by two other observations. Insulin treatment restores potentiation to normal in STZ-D rats (165,166), and the
same abnormality is found in a spontaneously occurring
diabetic rat model (167). The reason for the different
pattern in the pancreatectomy model is still puzzling.
That model has a milder level of hyperglycemia, which
may result in a less pronounced defect.
Quantitative morphometric studies were conducted to
ascertain (3-cell mass. In the pancreatectomized model,
P-cell mass 6 wk postsurgery was 42% of normal (152).
It was only 10% at the end of the surgery, so that impressive regeneration had taken place. Six weeks postSTZ, p-cell mass was 46% of normal (151). Again, there
was a period of active regeneration after the STZ. For
reasons that are still unexplained, the growth rate rises
soon after the insult but then slows after 2 wk, despite
continuing hyperglycemia. In this regard, we have primarily studied the pancreatectomy model and found a
gradual falling off of p-cell mass over time compared
with control rats (152,168). Interestingly, a ventromedial hypothalamic lesion again accelerates (3-cell replication, so that the falloff is not because the reserve
capacity is overextended (169). Instead, these results are



in agreement with the idea that a change in recognition

of the stimulus (glucose unresponsiveness) causes the
compensatory growth to slow.
Normal p-cell mass. We concluded that hyperglycemia
caused the glucose unresponsiveness in the other
models and that the only role served by the reduced (3cell mass was to cause the hyperglycemia. For further
proof, we turned to chronic glucose infusions in normal
rats, expecting to find similar results. Eight-week-old
200-g rats are infused with large amounts of glucose
through an indwelling catheter in the jugular vein (164).
Depending on the glucose concentration of the infusate,
blood glucose levels as high as 22.2 mM are attainable
for periods of up to 48 h. Thereafter, the level gradually
falls off (170). There are many unique advantages to this
model. The level of blood glucose and duration of the
infusion can be precisely controlled. This means that
the effects of varying degrees of hyperglycemia can be
compared. Also, the 3-cell mass starts out normal, so
that quantitative and qualitative insulin responses can
be assessed. Reversal studies are easily conducted by
simply turning off the pump and studying the rat after a
waiting period. Finally, plasma insulin levels rise along
with the blood glucose level, often to as much as 10
times normal (164). More traditional diabetic rat
models, including the two we initially studied, are hypoinsulinemic, making it impossible to separate out hyperglycemia causing the (3-cell dysfunction versus an
effect of insulin deprivation. The infused rats are hyperinsulinemic, so that shared defects effectively rule out
that possibility. The only disadvantage is that the infusions are relatively short term; in our laboratory, we
have not tried to carry them out beyond 96 h. Thus,
results are open to the criticism that they have little relevance to NIDDM where the p-cell defects evolve
slowly in the face of mild hyperglycemia. For this reason, all major observations are subsequently tested in
one of the other models.
Markedly hyperglycemic rats show insulin-secretion
characteristics that are identical to those described in
the models with reduced (3-cell mass (162,164,171): 7)
within 48 h insulin output is blind to changes in glucose
concentration, 2) arginine elicits large insulin responses,
3) glucose potentiation of arginine-induced insulin release is altered in a fashion identical to that of the STZD rats, and 4) the proinsulin-insulin ratio is increased
in pancreas extracts. (3-Cell morphometric results have
also mirrored the other models. f}-Cell replication is
markedly accentuated by the infusion (42). This last result is particularly interesting. Hyperglycemia is known
to be a potent stimulus for (3-cell growth (3,41). However, it is generally believed that fJ-cells of adult animals
have almost no growth potential. Instead, we found that
(3-cell mass rose 50% over the course of a 96-h infusipn
(42). When added to what we had observed in the
models with reduced p-cell mass (3- to 4-fold rise in (3cell mass during first few weeks after insult [151,152]),
it is clear that our concept of (B-cell growth potential
needs to be revised. Based on the other models, we


predict that the accelerated growth rate should wane

with time, but unfortunately, it is not possible to carry
infusions out that long.
To summarize, there is remarkable similarity between
the insulin secretion and p-cell morphometric characteristics of these models and those described previously
for NIDDM. We conclude that normal p-cells chronically exposed to hyperglycemia will invariably develop
functional defects characterized by glucose unresponsiveness. Moreover, the results in our rat models so
closely resemble what has been described in NIDDM
subjects that it is easy to conclude that the pathophysiology in both situations must be the same.
Modest hyperglycemia. The studies described previously in NIDDM subjects have clearly shown that glucose-induced insulin secretion is lost when the plasma
glucose level is only slightly above normal (90). We
have shown the same phenomenon in rats (17). Rats
underwent a 60% pancreatectomy, which, of itself, will
not raise glucose levels. Six weeks later, glucose-induced insulin responses were perfectly normal when
adjusted for the lower p-cell mass. In contrast, another
group was given 10% sucrose as their water supply.
Three weeks postsurgery, plasma glucose levels in these
rats rose by 0.84 mM and stayed at this level for the
duration of the experiment. Four weeks postsurgery,
glucose-induced insulin secretion was appropriate for
the (3-cell mass. In contrast, after another 2 wk, the
response was reduced 75%. These results are the first
to establish a direct link between (3-cell dysfunction and
minimal elevations in plasma glucose. Understanding
this fact strengthens the concept that the same mechanism can explain the glucose unresponsiveness in
NIDDM subjects.
The next major step was to show that hyperglycemia
and not some other metabolic effect of the diabetes was
causing the (3-cell dysfunction. The most direct evidence
comes from reversal studies. We found that 24 h of insulin treatment normalizes glucose potentiation in neonatal STZ-D rats, i.e., the exaggerated arginine response
at a low glucose background was no longer present
(165). In contrast, there was no improvement in glucose-induced insulin release. Kergoat et al. (166) did
get an improvement after 5 days of insulin. Studies such
as these are complicated by erratic glucose control. As
such, it is safe to state that insulin treatment can improve
glucose responsiveness, but caution must be used when
trying to glean much about specific details.
Reversal studies are considerably easier in the chronically infused rats; the infusion pump is simply turned
.off. Six hours postinfusion, glucose-induced insulin secretion is back to normal (172). The rats are hypoglycemic(4..4-5.5 mM) during that period. To see how the
same experimental conditions affected a model characterized by a longer duration of hyperglycemia, we
produced comparable hypoglycemia in 90%-pancreatectomized rats for 6 h with an insulin infusion. Again,



there was a marked improvement in glucose-induced

insulin release (172). Therefore, one kind of data supporting the deleterious effect of hyperglycemia is that
insulin treatment restores glucose responsiveness.
More direct evidence comes from the use of phloridzin. Phloridzin reduces renal tubular reabsorption of
glucose, so that diabetic animals are rendered euglycemic because of an increase in glycosuria (173). It can
be argued that the improvements noted with insulin
therapy could be because of the raised insulin level and
not because of the lowered glucose value. The advantage of phloridzin is that it is presumed to act selectively
only on the glucose concentration. Rossetti et al. (174)
found in 90%-pancreatectomized rats that 4 wk of
phloridzin improved both glucose-induced insulin secretion and glucose potentiation. The treatment was
started 2 wk postoperatively, so these results probably
represent prevention of secretory defects. We have
shown in glucose-infused rats that phloridzin can also
reverse preexisting secretory defects (170).
The third kind of evidence has been obtained in vitro
with the perfused pancreas. We reported in the STZ
model that perfusing the pancreas with a low glucose
concentration caused insulin output to paradoxically increase (161). It was as if the chronically elevated glucose level was holding insulin secretion in check.
Support for this last suggestion comes from Grill et al.
(175), who found that mannoheptulose, an inhibitor of
glucose phbsphorylation and therefore also of insulin
secretion, caused the same paradoxical rise in insulin
output. In that same article, they found that perfusing
the pancreas of diabetic rats with 0 glucose for 40 min
restored glucose's ability to induce an insulin response.
In contrast, 3.9 mM glucose did not have the same effect. We obtained identical results in the glucose-infusion model (unpublished observations).
Taken together, these results are consistent with hyperglycemia having an ongoing suppressive effect on
glucose responsiveness and that, in its absence, glucose
responsiveness rapidly returns. The results with 0 vs. 3.9
mM glucose deserve further comment. The improvement with 0 glucose cannot simply represent the glucose
level being returned to normal. If that were the case,
the same results with 3.9 mM glucose would have been
expected. Instead, the intracellular changes that restore
glucose responsiveness must occur at a rate that is inversely related to the ambient glucose concentration.
The nature of this relationship has yet to be defined.

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,



the first step in glucose metabolism. Malaisse (192) has

listed a number of other possibilities. An important focus
for future research will be to identify the biochemical
basis for the glucose unresponsiveness and to determine
how hyperglycemia ties in with it.


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,


normal body weight, and prudent diet. If these measures

are not sufficient, sulfonylureas or insulin is added. Clinicians are painfully aware that these therapies prove
inadequate in many patients. As we begin to unravel
the biochemical and genetic basis for the p-cell dysfunction and insulin resistance in NIDDM, we hopefully
will see the start of a new era, one in which novel therapies will be targeted at specific cellular abnormalities.


This work was supported by National Institutes of Health

Grants DK-38543, DK-35449, and DK-36836 (Diabetes
Endocrinology Research Center animal research core).

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