Annu. Rev. Med. 1996.

47:69–83
Copyright © 1996 by Annual Reviews Inc. All rights reserved

AN INTEGRATED VIEW OF β-CELL

DYSFUNCTION IN TYPE-II
DIABETES
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Vincent Poitout, D.V.M., Ph.D., and R. Paul Robertson, M.D.

The Diabetes Center, Division of Diabetes, Endocrinology, and Metabolism, University
of Minnesota, Minneapolis, Minnesota 55455

KEY WORDS: non-insulin-dependent diabetes, insulin secretion, pancreatic β-cell

ABSTRACT
Type-II (non-insulin-dependent) diabetes mellitus (NIDDM) is a heterogeneous
disease resulting from insulin resistance and β−cell dysfunction. β−Cell dys-
function in Type-II diabetes is characterized by a specific lack of first-phase
glucose-induced insulin secretion. This defect is readily reversible upon nor-
malization of blood glucose levels. Chronic hyperglycemia itself is harmful to
the β-cell and affects both insulin biosynthesis and exocytosis. No unique
intracellular defect has been demonstrated to be responsible for all common
forms of the disease. However, mutations of the glucokinase gene have been
identified in maturity onset diabetes in the young, a particular form of NIDDM.

INTRODUCTION
The pancreatic β-cell is a highly differentiated endocrine cell that synthesizes
and secretes insulin. Insulin promotes utilization of nutrients by peripheral
tissues and is the major circulating hormone capable of lowering blood glu-
cose levels and counteracting the effects of hyperglycemic hormones such as
glucagon, epinephrine, cortisol, and growth hormone. In nondiabetic individu-
als, blood glucose levels are maintained in a very narrow range (80–130
mg/dl), despite considerable variations in glucose availability. This implies
that the β-cell is able (a) to sense minute changes in blood glucose concentra-
tions, (b) to readily respond to those changes by immediate release of insulin,

0066-4219/96/0401-0069$08.00 69
 70 POITOUT & ROBERTSON

and (c) to modulate the rate of insulin biosynthesis according to secretory

needs. Fine-tuning of β-cell function is achieved by coordinate regulation of
insulin biosynthesis and exocytosis by nutrients, hormones, and autonomic
nervous system input. An alteration of this sophisticated network of regulatory
elements leads to dysregulation of glucose metabolism and chronic hypergly-
cemia.
Diabetes mellitus is characterized by chronic hyperglycemia caused by
absolute or relative insulin deficiency. Insulin-dependent diabetes mellitus
(IDDM, or Type I) is characterized by profound insulin deficiency resulting
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from a selective, immune-mediated destruction of pancreatic β-cells. Non-

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insulin-dependent diabetes mellitus (NIDDM, or Type-II) is generally a more

insidious condition that typically occurs in middle-aged to elderly individuals,
80% of whom are obese. Expression of the NIDDM phenotype results from a
combination of genetic predisposition (the concordance rate between homozy-
gotic twins is almost 100%) and environmental factors such as nutrition and
exercise and is characterized by peripheral insulin resistance and β-cell dys-
function. These two defects are of equal importance in the pathogenesis of
NIDDM, and both are necessary for the disease to occur (1).
Since β-cells are virtually absent in IDDM, this discussion focuses mainly
on the insulin secretory defects associated with NIDDM. Insulin resistance,
the other component of NIDDM, is beyond the scope of this chapter and is not
considered. However, it must be emphasized that a complete description of the
pathogenesis of Type-II diabetes should take into account both β-cell function
and insulin resistance. Insulin secretion in humans and its alterations in Type-
II diabetes is considered first, followed by a discussion concerning deleterious
effects of chronic hyperglycemia on β-cell function. Lastly, the biochemical
mechanisms by which glucose elicits insulin release and the intracellular de-
fects that have been postulated to play a role in the pathogenesis of NIDDM
are discussed.

INSULIN SECRETION IN HUMANS AND ITS

ALTERATIONS IN TYPE-II DIABETES

Glucose-Induced Insulin Secretion

Glucose is the primary stimulus for insulin secretion from the pancreatic
β-cell. In normal individuals, intravenous glucose elicits a biphasic insulin
release (Figure 1a). The first phase is sharp, reaches its maximum at 3–5 min,
and lasts approximately 10 min. The second phase is more blunted and lasts as
long as glucose levels remain elevated (2).
The major secretory defect associated with NIDDM is the absence of first-
phase insulin secretion in response to glucose (3) (Figure 1a). Brunzell et al
 β-CELL DYSFUNCTION IN TYPE-II DIABETES 71
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Figure 1 Insulin responses to intravenous administration of glucose (a) and arginine (b) in control
(left) and Type-II diabetic patients (right). Glucose-induced first-phase insulin release is absent in
NIDDM patients, whereas arginine-induced insulin secretion is preserved. IRI, Immunoreactive
insulin. (Adapted from Reference 8 with permission of the American Journal of Medicine.) _L

demonstrated that first-phase glucose-induced insulin release is lost in indi-

viduals with fasting plasma glucose levels above 115 mg/dl (4), providing
evidence that this secretory defect might be related to the ambient glucose
concentration.
A wide variety of physiologic and pharmacologic agents can modulate
glucose-induced insulin secretion. The major physiologic potentiators of glu-
cose-induced insulin secretion are glucagon and gastrointestinal peptides (in-
 72 POITOUT & ROBERTSON

cretins). Incretins have been named according to their ability to enhance the
level of circulating insulin after oral glucose intake. Glucagon-like peptide 1
(GLP-1) and gastric inhibitory peptide are two such incretins thought to play a
physiologic role. These hormones are very potent stimulators of glucose-
induced insulin secretion, and GLP-1 has been proposed as a new therapeutic
agent in NIDDM (see 5). Glucose-induced insulin secretion is inhibited by
epinephrine, somatostatin, prostaglandin E2, and galanin. Amylin, a polypep-
tide colocalized with insulin in the secretory granules and cosecreted with
insulin, has received increasing attention because it is a major component of
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the amyloid deposit found in the pancreas of NIDDM patients. Amylin has
been shown to modulate β-cell function (6), but the physiologic relevance of
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this observation has yet to be established.

Non-Glucose-Induced Insulin Secretion

Even though glucose is the most potent secretagogue for insulin secretion,
other agonists such as arginine, β-adrenergic agonists, glucagon, and secretin
can also elicit insulin responses.
The major defect in β-cell function observed in NIDDM patients is a lack of
insulin response to glucose but a retained ability to secrete insulin in response
to non-glucose secretagogues (Figure 1b). Robertson & Porte (7) first demon-
strated that isoproterenol was still able to elicit a first-phase insulin response,
indicating that the secretory defect in NIDDM lies in the glucose-recognition
process rather than in the secretory machinery. Further evidence for a selective
glucose unresponsiveness was obtained from experiments showing that other
non-glucose agonists (glucagon, arginine, secretin) stimulate first-phase insu-
lin release in diabetic patients (see 8 for a review).
Non-glucose stimulation of insulin secretion is potentiated by glucose, i.e.
the magnitude of the response to the stimulus increases as the prestimulus
glucose level is raised. This effect eventually reaches a plateau and is referred
to as glucose potentiation. It represents an adaptation of the β-cell secretory
response to changing metabolic demand. Glucose potentiation studies provide
a useful clinical assessment of β-cell function by two parameters: (a) the
glucose value at which the response is half-maximum (PG50), which reflects
glucose responsiveness; and (b) the maximum insulin response (AIRmax),
which assesses the secretory reserve of the β-cell (9). NIDDM patients show a
dramatic decrease in glucose potentiation of insulin response to non-glucose
secretagogues (9), the AIRmax to arginine being reduced by nearly 90%
(Figure 2) (10).

Pulsatility of Insulin Secretion

Under normal circumstances, diurnal insulin secretion follows an oscillatory
pattern with periods of 105–120 min (11). Oscillatory insulin infusions have
 β-CELL DYSFUNCTION IN TYPE-II DIABETES 73
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Figure 2 Acute insulin responses to arginine (AIRmax) at five plasma glucose levels in eight
NIDDM patients and eight control subjects. The AIRmax is decreased by nearly 90% in NIDDM
patients. (Adapted from Reference 10 with permission from the American Society for Clinical
Investigation.)

been demonstrated to be more efficient than continuous administration in

lowering plasma glucose levels (12). NIDDM patients show a decreased am-
plitude and a lack of regularity in insulin pulses after a meal. It has been
suggested that these defects contribute to the diminished insulin efficiency
observed in Type-II diabetes (11).

Proinsulin Levels
An altered maturation of proinsulin into insulin may exist in NIDDM patients.
During intracellular processing, proinsulin, the initial product of the insulin
gene, is cleaved into insulin and C peptide. In non-diabetic individuals, a small
percentage of proinsulin is not processed and is cosecreted with insulin. An
increased circulating proinsulin/insulin ratio has been found in patients with
Type-II diabetes and in first-degree relatives of patients with Type-I diabetes.
The cause for hyperproinsulinemia in such conditions is controversial: It could
represent either an increased β-cell demand and premature release of secretory
granules, or an actual defect in insulin processing (see 13 for a review).
Seaquist et al demonstrated an increased proinsulin/insulin ratio in patients
who had undergone hemipancreatectomy and have decreased β-cell secretory
reserve, indicating that hyperproinsulinemia in this instance is a consequence
of an increased β-cell demand (14). Furthermore, Alarcõn et al have recently
shown that proinsulin conversion rates are identical in a NIDDM rat and in
 74 POITOUT & ROBERTSON

control animals, further supporting the hypothesis that hyperproinsulinemia

results from increased demand rather than from an intrinsic processing defect
(15).
In summary, β-cell dysfunction in NIDDM is characterized by a lack of
first-phase insulin response to glucose. This secretory defect is specific for
glucose, since NIDDM patients retain the ability to secrete insulin in response
to other secretagogues. Other features of insulin secretion, such as glucose
potentiation of non-glucose-induced insulin release, diurnal pattern of insulin
secretion, and proinsulin/insulin ratio, are also altered in Type-II diabetes.
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EFFECTS OF CHRONIC HYPERGLYCEMIA ON β-CELL

FUNCTION
The hypothesis that hyperglycemia itself could be responsible for, or at least
contribute to, β-cell dysfunction has received considerable attention for the
last two decades. This phenomenon is often referred to as glucose desensitiza-
tion or glucose toxicity. As discussed below, these terms actually describe
different phenomena.

Studies in Type-II Diabetic Patients

The first evidence that chronic hyperglycemia itself can adversely affect β-cell
function came from experiments in NIDDM patients in which restoration of
glucose-induced insulin secretion was obtained following normalization of
blood glucose levels for short periods of time. As early as 1976, Turner et al
observed a 2.5-fold increase in glucose-induced first-phase insulin secretion
after lowering plasma glucose levels to 74 mg/dl in diabetic patients (16).
Vague & Moulin were able to demonstrate partial restoration of glucose-in-
duced insulin response after 20 h of insulin infusion in hyperglycemic Type-II
diabetes patients (Figure 3) (17). As quoted earlier, Brunzell et al (4) also
demonstrated in humans a threshold plasma glucose level of 115 mg/dl above
which first-phase glucose-induced insulin secretion is lost. Interestingly, phar-
macologic maneuvers other than insulin infusions are also able to restore
glucose-induced insulin secretion in NIDDM patients: Phentolamine, nalox-
one, and sodium salicylate have been shown to partially restore glucose-
induced first-phase insulin release. This suggests that glucose unresponsive-
ness could in part be mediated by catecholamines, opioids, or prostaglandins
(see 18). These studies clearly point to the central role that chronic hyperglyce-
mia plays in the secretory defects associated with NIDDM and demonstrate
that glucose-induced insulin release is readily and at least partly restored upon
normalization of plasma glucose levels or treatment with various pharma-
cologic agents.
 β-CELL DYSFUNCTION IN TYPE-II DIABETES 75
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Figure 3 Insulin responses to intravenous glucose and intravenous tolbutamide before and after a
20-hr insulin infusion in NIDDM patients. First-phase glucose-induced insulin secretion was
partially restored following normalization of plasma glucose levels, whereas insulin response to
tolbutamide was unchanged. FPG, Fasting plasma glucose. (Adapted from Reference 17 with
permission of WB Saunders Co.)

Studies in Animal Models of Type-II Diabetes

Studies in animal models of Type-II diabetes have provided further evidence
that hyperglycemia per se induces loss of glucose-induced insulin secretion.
Rats made hyperglycemic by neonatal streptozotocin administration, 90% pan-
createctomy, or chronic intravenous glucose infusions show selective loss of
glucose-induced insulin secretion yet are still able to secrete insulin in re-
sponse to non-glucose secretagogues. Male Zucker fa/fa rats become sponta-
neously hyperglycemic and glucose unresponsive, whereas female Zucker
fa/fa retain normoglycemia and secrete insulin in response to glucose. Rats
 76 POITOUT & ROBERTSON

that underwent a 60% pancreatectomy are normoglycemic and retain normal

glucose-induced insulin release. However, when these rats are given su-
crose-enriched drinking water they become hyperglycemic and no longer
secrete insulin in response to glucose (see 19). Several experimental maneu-
vers have been utilized in these animals to restore normoglycemia and thus to
reverse the insulin secretory defect. Phlorizin, an inhibitor of kidney tubule
glucose reabsorption, has been used in hyperglycemic rats to specifically
lower blood glucose levels without changing plasma insulin levels. Rats with a
90% pancreatectomy treated with phlorizin recover their ability to secrete
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insulin in response to glucose (20). Normalization of blood glucose levels by

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insulin treatment also leads to recovery of glucose-induced insulin secretion.

For example, Leahy & Weir have shown that a 6-hr insulin infusion in 90%
pancreatectomized rats was sufficient to induce a fourfold increase in glucose-
induced insulin response (21).

Glucose Desensitization Versus Glucose Toxicity

Recently, several groups of investigators have attempted to define a mecha-
nism for the deleterious effect of hyperglycemia on β-cell function. A thor-
ough examination of these studies clearly allows for differentiating glucose
desensitization from glucose toxicity: The first is a reversible impairment of
insulin secretion; the second is an irreversible defect in insulin synthesis.
An important question that arises is whether hyperglycemia-induced lack of
glucose-stimulated insulin response results from “true” desensitization,
namely an alteration in stimulus-secretion coupling, or from depletion of intra-
cellular insulin stores (“exhaustion”) as a consequence of chronic stimulation.
Sako & Grill (22) addressed this issue by comparing insulin secretion from rat
pancreas after a 48-h glucose infusion in the presence or absence of diazoxide,
an inhibitor of insulin release. They observed preservation of insulin secretion
when diazoxide was given with glucose and concluded that the absence of
glucose-induced insulin release associated with hyperglycemia is caused by
non-specific exhaustion of the β-cell. Similarly, Kaiser et al (23) exposed rat
islets for several weeks to either high glucose concentrations or a lower glu-
cose concentration plus IBMX (3-isobutyl-1-methylxanthine), a potentiator of
glucose-induced insulin secretion, and showed that insulin secretion was
markedly reduced in both conditions and was reversible by reducing glucose
concentration in the culture medium. Conversely, Davalli et al (24) demon-
strated that human islets of Langerhans cultured in high glucose concentra-
tions for 48 h are not able to subsequently secrete insulin in response to
glucose but retained normal arginine-induced insulin release, which favors a
glucose-specific desensitization effect. Bedoya & Jeanrenaud (25) also
showed a selective impairment of glucose-induced insulin secretion in islets
from rats that had been made hyperglycemic for 1 week. Finally, Eizirik at al
 β-CELL DYSFUNCTION IN TYPE-II DIABETES 77

(26) observed diminished insulin content and defective insulin secretion from
human islets cultured in high glucose concentrations for 7 days. These changes
were partially reversed by subsequent culture in lower glucose concentrations.
These studies clearly support the concept that exposure of β-cells to high
glucose concentrations impairs their ability to secrete insulin in response to
glucose. It is unclear whether this phenomenon reflects true desensitization or
β-cell exhaustion. Nonetheless, this defect is detectable even after short-term
exposure to high glucose, is readily reversible upon normalization of glucose
levels, is likely to involve the exocytotic apparatus, and is properly referred to
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as glucose desensitization (27).

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In contrast, several studies have focused on potential long-term, irreversible

effects of elevated glucose levels on β-cell function. Orland & Permutt (28)
evaluated circulating insulin levels as well as pancreatic insulin content and
mRNA levels in db/db mice, a spontaneous model of NIDDM. db/db mice fed
ad libitum showed an increase in blood glucose from 200 to 400 mg/dl and a
decrease in circulating insulin from 10 to 1 ng/ml between 5 and 13 weeks of
age, whereas both blood glucose and insulin remained in the normal range in
control (+/db ) mice over the same period. Analysis of intracellular insulin
content and insulin mRNA levels in pancreatic aliquots showed less intracellu-
lar content over time and a dramatic decrease in insulin mRNA levels. The
authors concluded that several weeks of hyperglycemia lead to a decrease in
insulin gene expression. Robertson et al (29) chronically cultured HIT cells, a
β-cell line derived from SV40-transformed Syrian hamster islets, in various
glucose concentrations for several months and assessed insulin mRNA levels.
A profound decrease in insulin mRNA levels was observed in HIT cells
cultured for 25 weeks in 200 mg of glucose per dl; when the cells were grown
in 15 mg of glucose per dl, this decrease was prevented. Olson et al demon-
strated that this decrease in insulin gene expression was associated with defec-
tive expression and/or binding of nuclear proteins that regulate insulin gene
transcription (30–32). These changes were not reversed by subsequent culture
in low glucose concentrations for an additional 25 weeks (LK Olson et al,
unpublished observations). These studies indicate that long-term exposure of
β-cells to high glucose concentrations can have irreversible, toxic effects on
insulin gene expression. This phenomenon is thus clearly different from glu-
cose desensitization and should be referred to as glucose toxicity (27).
The distinction between glucose desensitization and glucose toxicity is
clinically important: The former can account for the readily reversible, glu-
cose-specific impairment of first-phase insulin secretion observed in NIDDM
patients; the latter could explain why glucose-induced insulin release is never
completely restored following normalization of glucose levels, and why insu-
lin responses to non-glucose secretagogues are not perfectly normal in
NIDDM patients. In addition, glucose toxicity might be an explanation for
 78 POITOUT & ROBERTSON

so-called secondary drug failure seen in NIDDM patients treated with sulfony-
lureas who have been hyperglycemic for two or three decades.

INTRACELLULAR DEFECTS IN TYPE-II DIABETES

Newly available tools in cellular and molecular biology have made it possible
to search for defects in cellular function that could explain defective insulin
secretion in NIDDM. Several abnormalities in β-cell physiology have been
identified, but none of them seems to represent a generalized phenomenon that
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could account for all common forms of the disease. In fact, it is highly unlikely
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that NIDDM will ever be explained by a single cellular defect. Type-II diabe-
tes is a heterogeneous disease that results from the combination of a genetic
susceptibility thought to be polygenic and numerous environmental factors.
Nonetheless, tremendous progress has recently been made toward under-
standing intracellular mechanisms underlying Type-II diabetes in particular
forms of the disease. These studies are reviewed in this last section after a
short consideration of biochemical events that lead to glucose-induced insulin
release.

Biochemistry of Glucose-Induced Insulin Secretion

Glucose metabolism within the β-cell is required to induce an insulin secretory
response. Glucose enters the cell through the low affinity–facilitated glucose
transporter GLUT 2. The high Km and Vmax of GLUT 2 allow for rapid
equilibration across the β-cell membrane. Glucose is then phosphorylated into
glucose-6-phosphate by glucokinase, an isoform of hexokinase whose high Km
ensures that glucose phosphorylation rates are proportional to blood glucose
levels. Glucose phosphorylation is thought to be a major rate-limiting step in
glucose metabolism within the β-cell, thus playing an essential role in normal
glucose-induced insulin secretion (31, 32). Glucose-6-phosphate is then meta-
bolized through glycolysis and the Krebs cycle. According to the most widely
accepted hypothesis, the resulting increase in the adenosine triphosphate
(ATP):adenosine diphospate ratio leads to inhibition ( closure ) of ATP-sensi-
tive (L-type) K+ channels, membrane depolarization, and activation of volt-
age-dependent Ca2+ channels (34). However, several groups of investigators
have raised convincing arguments against the role of whole-cell ATP concen-
tration as an effector of K+ channels. This issue remains to be clarified (35).
Opening of the voltage-gated Ca2+ channel leads to an increase in intracellular
Ca2+ concentration, which in turn triggers a cascade of protein phosphoryla-
tions that probably involves the Ca2+/calmodulin class of kinases and results
in insulin exocytosis (36) (Figure 4). Despite several decades of intensive
investigation, no unifying hypothesis is available to fully explain glucose-in-
duced insulin secretion. Neither changes in intracellular cyclic adenosine mo-
 β-CELL DYSFUNCTION IN TYPE-II DIABETES 79

nophosphate concentrations nor activation of protein kinase C seem to directly

mediate the effects of glucose, and the potential roles of inositol phospholipid
hydrolysis, nitric oxide synthesis, or arachidonic acid metabolism need further
investigation (37).

Intracellular Defects in Type-II Diabetes

INSULIN GENE MUTATIONS Mutations of the insulin gene have been identified
in several families with non-insulin-dependent diabetes (38). Such mutations
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can lead either to a biologically defective insulin molecule, resulting in a mild

diabetic state or glucose intolerance, or to a defective proinsulin molecule that
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exhibits impaired cellular processing and maturation. These observations, how-

ever, are relevant only to a very small portion of diabetic patients.

Figure 4 Schematic representation of the intracellular events involved in glucose-induced insulin

release. Glucose is transported into the cell through the facilitated transporter GLUT-2 and is then
phosphorylated by the high Km glucokinase. Metabolism of glucose results in closure of adenosine
triphosphate (ATP)-sensitive K+ channels, membrane depolarization, and opening of voltage-gated
Ca2+ channels. This in turn triggers a cascade of protein phosphorylations and leads to insulin
exocytosis.
 80 POITOUT & ROBERTSON

GLUCOSE TRANSPORT GLUT-2 expression is decreased in several rodent mod-

els of mice with Type-II diabetes. However, it has not been proved that a
reduction in GLUT-2 levels is responsible for the lack of glucose-induced
insulin release. A strong argument against this hypothesis is that the rate-limiting
step of glucose metabolism is glucose phosphorylation and that glucose trans-
port capacity of the β-cell exceeds by 10-fold that of glucose phosphorylation.
In addition, it is not clear whether or not the actual rate of glucose transport is
reduced in animals with Type-II diabetes (see 39 for a review).
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GLUCOSE PHOSPHORYLATION The hypothesis that glucose phosphorylation

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could be altered in NIDDM is more tempting than hypotheses concerning

defective glucose transport because phosphorylation represents a limiting step
of glucose metabolism within the β-cell. Indeed, it has recently been shown that
mutations in the glucokinase gene are associated with a mild form of NIDDM,
maturity onset diabetes in the young (MODY), which occurs earlier in life than
typical Type-II diabetes. Glucokinase mutations have been found in 56% of the
French families with MODY (40). Mutations of the glucokinase gene translate
into a decreased sensitivity of the β-cell to glucose (41). Interestingly, patients
with glucokinase mutations have preserved first-phase insulin responses to
glucose (41), perhaps because their β-cells are insensitive to the deleterious
effect of chronic hyperglycemia observed in late-onset NIDDM. The linkage
between mutations in the glucokinase gene and a significant proportion of
MODY patients provides the first example of a mutation in a single gene of
glucose metabolism associated with a common form of Type-II diabetes.

GLUCOSE METABOLISM AND IONIC EVENTS An extremely rare form of

NIDDM associated with deafness has been linked to a point mutation of a
mitochondrial gene (42). Along the cascade of intracellular events distal to
glucose phosphorylation that lead to insulin secretion, several steps have been
implicated as being potentially altered in animal models of Type-II diabetes or
in vitro systems. Defects in mitochondrial oxidation, membrane phospholipid
hydrolysis, and K+ channel function have been associated with chronic hyper-
glycemia, but the clinical relevance of these observation has yet to be determined
(see 19 for a review).

CONCLUSIONS
Insulin secretion from the pancreatic β-cell is a highly regulated process that
maintains blood glucose levels within a very narrow range. Glucose homeosta-
sis is achieved by a complex interplay between nutrients, hormones, and the
autonomic nervous system. Non-insulin-dependent diabetes results from a
combination of peripheral insulin resistance and β-cell dysfunction. β-Cell
 β-CELL DYSFUNCTION IN TYPE-II DIABETES 81

function in non-insulin-dependent diabetes is characterized by a specific lack

of first-phase glucose-induced insulin secretion, readily and at least partially
reversible following normalization of blood glucose levels. Whatever the
original defect is, hyperglycemia itself is deleterious to the β-cell and contrib-
utes to the aggravation of the disease over time. Our perspective is that ele-
vated glucose adversely affects β-cell function by at least two mechanisms: (a)
Repeated exposure to the glucose signal desensitizes the exocytotic machinery
and leads to a reversible lack of insulin response to glucose; and (b) chronic
exposure of β-cells to high glucose concentrations is irreversibly toxic to the
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insulin gene. This suggests that NIDDM patients should benefit from better
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glycemic control. Despite intensive investigation, no single intracellular defect

has been identified as being responsible for β-cell dysfunction in all common
forms of NIDDM. Indeed, it is unlikely that this will ever be the case because
NIDDM is a heterogeneous disease that probably involves a combination of
multiple defects. The discovery that a mutation of the glucokinase gene is
associated with a particular form of the disease is, however, of critical impor-
tance. It provides the first evidence that a mutation of a single gene of glucose
metabolism can lead to non-insulin-dependent diabetes.

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