Download Toward a Systems Biology of Insulin Secretion and Type 2 Diabetes

Editorial
Toward a Systems Biology of Insulin Secretion and Type 2
Diabetes
Donald F. Steiner,1 Christian Boitard,2 Erol Cerasi,3 Suad Efendic,4 Jean-Claude Henquin,5
and Ele Ferrannini6
A
lthough it is clear that ␤-cell pathology, in
particular disordered insulin secretion, is a key
underlying pathogenetic feature of most forms
of diabetes, complex interactions of the islets
with other organs, such as brain, liver, gut, and several
peripheral tissues, are also essential for the normal integration of metabolism. It is this area that has been
explored in the Seventh Annual Servier-IGIS Meeting,
which was held last Spring in St. Jean Cap Ferrat in
Southern France. The focus of these meetings, since their
inception in 2000, has been the ␤-cell and the mechanisms
underlying its development and function as the source of
insulin, the most essential regulator of the blood glucose
level.
The familiar pathways of glucose, lipid, and amino acid
metabolism in humans and other mammals are, of course,
fundamental to almost all organisms, except perhaps for
the most highly specialized bacteria, so it is not surprising
that insulin-like molecules and the insulin/IGF receptor
signaling system are well conserved features of all metazoans that have been studied. With the rise of multicellular
organisms in evolution came the need to regulate and
coordinate metabolism and growth in order to maintain
both the constancy of the internal environment (homeostasis) and also to respond to the external environment. One of the most prominent environmental stimuli
had to be the availability of nutrients and fuels for survival
and growth. The insulin-like hormones, insulin and IGF,
appear to have evolved, along with a panoply of other
regulatory substances, to fine-tune the efficient uptake,
From the 1Departments of Biochemistry and Medicine, University of Chicago,
Chicago, Illinois; 2Institut National de la Santé et de la Recherche Médicale
U561, St. Vincent de Paul Hospital, Paris, France; the 3Department of
Endocrinology and Metabolism, Hebrew University Hadassah Medical Center,
Jerusalem, Israel; the 4Department of Molecular Medicine, Division of Endocrinology & Diabetes, Karolinska Hospital, Stockholm, Sweden; the 5Unit of
Endocrinology and Metabolism, University of Louvain, Brussels, Belgium; and
the 6Metabolism Unit, CNR Institute of Clinical Physiology, University of Pisa,
Pisa, Italy.
Address correspondence and reprint requests to Donald F. Steiner. E-mail:
[email protected].
CNS, central nervous system; FFA, free fatty acid; FFAR, free fatty acid
receptor; GBS, gastric bypass surgery; GIP, gastric inhibitory polypeptide;
GLP, glucagon-like peptide; HGP, hepatic glucose production; IL, interleukin;
KATP channel, ATP-sensitive K⫹ channel.
The symposium and the publication of this editorial have been made
possible by an unrestricted educational grant from Servier, Paris.
DOI: 10.2337/db06-S000
© 2006 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006
storage, and utilization of nutrients for either energy
production or growth.
Appropriately, the symposium opened with an introductory lecture by Leopold, reviewing our current knowledge
of the control of metabolism and growth in the fruit fly,
Drosophila melanogaster, by insulin-like peptides and an
insulin signaling pathway that is remarkably similar in
many of its components to that of man. No less than seven
Drosophila insulin-like peptides have been found. Three of
these are expressed in specialized neurones in the insect
brain, while others are expressed in larval tissues during
development. Insulin-like peptides released from the brain
cells downregulate hemolymph sugar levels, while a glucagon-like peptide, the adipokinetic hormone, from other
neuroendocrine structures opposes it by raising sugar
levels. Interestingly, these adipokinetic hormone-producing cells, unlike the insulin-producing cells, express an
ATP-sensitive K⫹ channel (KATP channel) that responds to
tolbutamide to increase their secretory activity, resulting
in hyperglycemia. Moreover, mutations that influence
components of the insulin receptor pathway result in
reduced growth, reflected in smaller cells in smaller
adults. Impaired insulin signaling also results in increased
longevity, decreased reproduction, and increased stress
resistance. Complex interactions with other endocrine
(ecdysone, juvenile hormone) and metabolic (TOR, etc.)
pathways integrate nutrition and metabolism and eventual
organismal size. The powerful genetic tools available for
Drosophila make it a rich experimental source for identification of new components of these important conserved
pathways.
Much recent work has focused on the role of lipids as
modulators of insulin action and as important factors in
the pathogenesis of type 2 diabetes via induction of insulin
resistance. Shulman and coworkers have used magnetic
resonance spectroscopy to explore the molecular mechanisms underlying defective glucose transport and glycogen
metabolism in muscle. Increased lipid metabolites such as
fatty acyl-CoAs and diacylglycerol activate kinase cascades that impair insulin signaling due to Ser/Thr phosphorylation of IRS-1. Similar mechanisms may operate to
impair hepatic insulin signaling due to increased hepatic
lipids in insulin-resistant subjects. These changes then
lead to relative increases in gluconeogenesis and reduced
hepatic glucose uptake via lowered AKT2 and increased
FOXO transcriptional effects on several key gluconeogenic
rate-controlling enzymes. In related magnetic resonance
spectroscopy studies, significant decreases in mitochondrial oxidative phosphorylation activity in muscles and
liver have been found in elderly, lean, insulin-resistant
volunteers, in association with increased muscle and heS1
D.F. STEINER AND ASSOCIATES
patic lipid content. Similar changes were found in young,
lean offspring of parents with type 2 diabetes associated
with reduced mitochondrial density, consistent with other
reported studies. The mechanisms underlying the reduction in mitochondrial biogenesis in these individuals is an
important area for further study that may lead to new
targets for therapeutic intervention.
While lipid overload can lead to insulin resistance and
impaired ␤-cell function, fatty acids and other lipids are
also important for normal ␤-cell function. It is well established that fatty acids can augment glucose-stimulated
insulin secretion, an effect that may be especially important in meeting the demands for increased insulin in
compensated insulin resistance. Lipids can act both
through their metabolism as well as via free fatty acid
(FFA) receptor (FFAR) activation. Prentki and associates
have studied these mechanisms in detail and find that
increased cytosolic malonyl-CoA arising from glucose and
lipid metabolism acts via AMPK/malonyl-CoA pathways to
limit fatty acid oxidation, thus increasing long-chain acylCoA signaling molecules. Glucose can then enhance esterification and subsequent lipolysis of long-chain acyl-CoA
to renew the FFA pool, which can then interact with
FFAR/GPR40, enhancing cytosolic Ca2⫹ and insulin secretion. Glucose may also enhance release of arachidonic
acid from phospholipids to activate yet other lipid-signaling pathways in the ␤-cell.
Since many of the foregoing effects of lipids on insulin
secretion depend on glucose-stimulated lipolytic activity,
efforts are currently underway to identify ␤-cell lipases.
Indeed, orlistat, a lipase inhibitor, abolishes lipolysis of triand diglycerides in islets, inhibiting insulin secretion without perturbing glucose metabolism. Mulder and colleagues
have examined hormone-sensitive lipase–null mice but
find no evidence of a ␤-cell secretory effect. Thus, further
studies to identify the role of other lipases involved in
␤-cell stimulus-secretion coupling are needed.
In addition to substrates such as FFA, various adipokines such as tumor necrosis factor-␣ and resistin are
associated with obesity and insulin resistance, whereas
others such as leptin and adiponectin sensitize the body to
insulin. Adiponectin has been shown to be upregulated by
thiazolidinediones acting through peroxisome proliferator–activated receptor-␥. As reviewed by Kadowaki and
associates, adiponectin circulates in several multimeric
forms, of which the high–molecular weight forms are most
active in ameliorating insulin resistance through negative
effects on hepatic gluconeogenesis and lowering of FFA
through stimulation of skeletal muscle FFA oxidation. He
and his associates have carefully dissected the effects of
pioglitazone dosage on ob/ob and adipo⫺/⫺ ob/ob mice to
demonstrate both adiponectin-dependent and -independent pathways of thiazolidinedione action on such parameters as adipocyte size and adiponectin production, as well
as target organ effects on hepatic AMPK activation and
decreased gluconeogenesis, leading to improved glucose
tolerance and diabetes control.
In a session on muscle and liver, Newsholme and
colleagues discussed the effects of amino acids on key
␤-cell processes leading to enhanced insulin secretion,
with special emphasis on generation of ATP and the
mechanisms coupling amino acid metabolic pathways
with the putative generation of messengers of mitochondrial origin.
Turning to factors arising from muscle, interleukin
(IL)-6, a cytokine having both pro- and anti-inflammatory
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actions, is released in large amounts during exercise.
Increases in IL-6 production and secretion are associated
with increases in AMPK activity in tissues such as muscle
and adipose tissue. AMPK enhances ATP generation while
inhibiting nonessential energy consuming processes via
phosphorylation of selected metabolic enzymes. Ruderman and colleagues have demonstrated decreased AMPK
activity in muscle and adipose tissue in young IL-6 –null
mice and a diminished enzyme response to exercise in
these tissues. These animals later develop manifestations
of the metabolic syndrome with obesity, dyslipidemia, and
impaired glucose tolerance. Key questions are whether
these effects of IL-6 contribute to the reported benefits of
exercise in reducing the prevalence of type 2 diabetes,
coronary atherosclerosis, and other concomitants of the
metabolic syndrome in humans.
In liver, as in the ␤-cell, glucokinase plays a key role as
a glucose sensor. However, the complex conformational
states and regulatory networks that control glucokinase
function differ significantly in these two tissues. As discussed by Baltrusch and Tiedge, these range from the use
of alternate promoters to regulate enzyme expression and
the shuttling of a high-affinity regulatory protein between
cytosol and nucleus in the liver to altered compartmentalization of glucokinase in ␤-cells and its activation by
binding of the bifunctional enzyme 6-phosphofructo-2kinase/fructose-2,6-biphosphatase (PFK-2/FBPase-2) to increase its Vmax. Some of these effects, and those of
chemical glucokinase activators, are related to various
conformational states with altered catalytic activity, as
revealed in recent crystallographic studies.
This session ended with consideration of the timehonored conundrum as to whether the inhibitory effect of
insulin on hepatic glucose production (HGP) is direct or
indirect. Girard carefully reviews the various known indirect influences on HGP, which include suppression of
glucagon levels, plasma nonesterified fatty acid or gluconeogenic precursors from peripheral tissues, along with
more recent studies on effects of various adipokines, as
well as novel central mechanisms. Infusion of insulin into
the third ventricle has been shown to inhibit HGP, an
effect reversed by inhibition of insulin receptor signaling.
Surprisingly, central infusion of activators of KATP channel
lowered blood glucose levels by inhibiting HGP, while
KATP inhibitors reduced the effects of systemic insulin.
These effects are mediated via the hepatic branch of the
vagus nerve. However, recent studies with mice lacking
expression of insulin receptor only in liver, as well as
clamp studies on dogs, support direct effects of insulin as
being of more paramount importance in suppressing HGP.
Girard proposes that the relative importance of glycogenolysis versus gluconeogenesis in various experimental
protocols may account in part for various reported species
differences in sensitivity to direct versus indirect effects.
Moreover, as gluconeogenesis is less sensitive to suppression by insulin than glycogenolysis in type 2 diabetes,
therapeutic agents that suppress glucagon hypersecretion,
such as glucagon-like peptide (GLP)-1 and/or others,
should likely be clinically beneficial for lowering HGP.
The gastrointestinal tract has recently proven to be a
rich source of promising endocrine substances with antidiabetic effects. GLP-1, a product of the glucagon gene, is
produced in the intestinal L-cells through the action on
proglucagon of prohormone convertase (PC)1/3, in contrast to the islet ␣-cells, where PC2 acts to process mainly
glucagon from the same precursor. GLP-1 has emerged as
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006
EDITORIAL
an important incretin hormone, augmenting the effects of
oral nutrient stimuli on insulin release. The factors that
regulate GLP-1 secretion are clearly of considerable interest, in view of its recently demonstrated efficacy in treating
type 2 diabetes. Its actions include potentiation of insulin
secretion in response to glucose, enhancement of ␤-cell
growth and survival, and inhibition of glucagon secretion,
gastric emptying, and food intake. Both nutrients and
various non-nutrient peptides and neuromodulators have
been implicated in GLP-1 release, as discussed in reviews
by Brubaker and Reimann and coworkers in this session.
Clearly, elucidation of these pathways could lead to the
development of therapeutic GLP-1 secretogogues.
Gastric inhibitory polypeptide or glucose-dependent insulinotropic peptide (GIP), another member of the glucagon family produced in the intestinal K-cells, exerts
incretin effects, both directly on the ␤-cell and via augmentation of GLP-1 secretion and/or action. Seino and collaborators have studied effects of GIP receptor knockout in
mice and found reduced incretin effects on glucose-induced insulin secretion, a defect that is additive with that
induced by GLP-1 receptor knockout. These investigators
have also documented extra-pancreatic effects of GIP on
the accumulation of fat in adipose tissue and of calcium
into bone, indicating a broader role for this gut-derived
peptide in regulating nutrient uptake. These effects suggest that GIP is the product of a “thrifty gene” and thus
may contribute to the incidence of obesity and diabetes.
Crossing GIP receptor–null mice with leptin-deficient
ob/ob mice resulted in significant amelioration of obesity
and dyslipidemia, accompanied by increased insulin sensitivity and glucose tolerance. The authors conclude that
effects of both GIP receptor agonists and/or antagonists
may provide beneficial effects in certain forms of diabetes.
Another approach to therapy of obesity and/or type 2
diabetes is gastric bypass surgery (GBS) and related
surgical procedures. Naslund and Kral review the effects
of GBS with special emphasis on its effects on gastrointestinal peptide levels, including ghrelin and three incretin
hormones—GLP-1, GLP-2, and peptide YY. This approach
to therapy in a majority of cases is curative and results
generally in reduced ghrelin levels and enhanced incretin
effects, which likely contribute to the favorably altered
physiologic state induced by GBS. Alterations in adipokines and neuroregulatory circuits may also contribute to
its positive effects.
The islets are the focus of a larger number of peripheral
and central inputs in addition to those discussed above.
The islets are richly innervated by both parasympathetic
and sympathetic nerve fibers, which act through the
classical neurotransmitters acetylcholine and norepinephrine, respectively, which exert either stimulatory or inhibitory effect on the ␤-cells. A variety of neuroregulatory
peptides also modulate both insulin and glucagon secretion. The latter are the major focus of a comprehensive
review by Ahren and coworkers. The possibility of altered
islet innervation in various models of insulin resistance
and type 2 diabetes has been investigated by these authors
in several animal models of diabetes (GK rats and db/db
mice) with findings indicative of increased islet innervation. They propose that “augmented expression of neurotransmitters in the islets is a sign of islet adaptation for
normalization of glucose tolerance” and conclude that
further exploration of this area may yield new insights into
neural mechanisms that contribute to the regulation of
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006
both islet cell mass and function in normal and pathologic
states.
Another aspect of extrinsic inputs into glucose sensing
in the regulation of insulin secretion has been explored
recently by Thorens and associates who have developed
ingenious methods to identify and study extrapancreatic
glucose sensors in both the hepatoportal vein and the
central nervous system (CNS). The hepatoportal sensor is
activated by glucose gradients between the portal vein and
peripheral veins and transmits signals via afferent
branches of the hepatic vagal nerve to the CNS. It affects
both first-phase insulin secretion and peripheral insulin
sensitivity via a variety of pathways. Both extrapancreatic
sensors are dependent on GLUT2 expression for their
normalizing effects, including those on feeding behavior
and glucagon secretion. Identification of their precise
localization may provide new insights into the physiology
of energy intake and metabolism.
In addition to peripheral glucose sensors, the brain has
emerged as a central switchboard, integrating signals from
many regions of the body (liver, gut, adipose tissue, and
islets) conveyed by afferent nerves and neurotransmitters,
as well as by circulating hormones and the major nutrients
(glucose, amino acids, and free fatty acids) to regulate
energy homeostasis, food intake, reproduction, and even
learning and memory. The reports in this section are
focused on various aspects of this expanding area of great
current interest.
Needless to say, insulin and leptin are key players in this
informational game, and they act primarily via receptors
localized in hypothalamic centers such as the arcuate
nucleus that control feeding behavior, satiety, and energy
expenditure. Elevated insulin and leptin signal the availability of excess nutrients and thus tend to reduce food
intake and enhance energy expenditure, as discussed by
Wood and his coworkers. They point out that insulin with
its rapid fluctuations in secretion and short half-life is a
monitor of blood glucose and ongoing metabolism, as well
as of body adiposity, while leptin’s longer half-life and
secretion from adipocytes conveys information on both fat
stores and adipocyte metabolic activity. Centers in the
arcuate nucleus regulate satiety and respond to these
anorexigenic signals by downregulating secretion of orexigenic factors such as neuropeptide Y and agouti-related
peptide and upregulating the release of other factors
promoting anorexia, such as ␣-MSH (melanocortin) and
CART (cocaine- and amphetamine-related transcript).
Other peripheral orexigenic hormones, especially ghrelin,
are released from the stomach and upper gut before
mealtimes and tend to oppose waning insulin/leptin actions in the hypothalamus, stimulating new cycles of
feeding. Woods et al. also discuss possible consequences
of insulin signaling in the hippocampus in relation to
cognitive function, pointing out the possibility that enhanced learning may facilitate foraging for food. Olfactory
insulin signaling may likewise enhance associations between certain foods and specific odors. Clearly, the development of obesity and insulin resistance may also occur
centrally, resulting in impairment of normal regulatory
processes, as well as cognitive functions.
Levin and coworkers go on to consider in greater detail
the properties of glucose-sensing neurons, both inhibitory
and excitatory. In early classical studies of the hypothalamus using lesions or electrical stimulation, certain areas
were associated with food intake and energy expenditure.
Lesions of the ventromedial hypothalamus led to hyS3
D.F. STEINER AND ASSOCIATES
perphagia and obesity, while lesions in the lateral hypothalamic area reduced food intake and increased
autonomic activity, leading to lower body weight. Glucosesensing neurons are widely distributed in forebrain and
brainstem nuclei, where they integrate both “hard-wired”
inputs from the periphery with hormonal, neuropeptide,
and substrate signals. These populations appear to express glucose-sensing systems, such as glucokinase and
KATP channels, similar to those of normal ␤- and ␣-cells.
They respond to other stimuli such as lactate from glial
cells, fatty acids, and ketone bodies, as well as to both
insulin and leptin. Their output, in combination with other
glucose-sensing neurones, is via a variety of efferent neural
pathways that impact all aspects of energy homeostasis—
intake, storage, and expenditure.
An interesting related issue, reviewed by Pénicaud and
colleagues, is the discovery of the expression of the
translocatable glucose transporter GLUT4 and more recently the related transporter, GLUT8, in the brain. These
appear to function by translocation from intracellular
pools to the plasma membrane, and their expression has
been reported to be influenced by glucose and insulin, but
whether they respond to insulin in a classical manner is
still controversial. GLUT8 has also been noted to translocate to the endoplasmic reticulum, suggesting a possible
role in glycoprotein biosynthesis and/or degradation. Gene
disruption strategies are needed now to shed new light on
the potential physiological roles of these transporters in
regulating the brain’s metabolism and/or signaling functions.
In addition to glucose, FFAs are well known to influence
carbohydrate metabolism and energy homeostasis via
central mechanisms. This area is nicely reviewed by
Magnan and coworkers. These authors have previously
shown that infusion of lipids such as oleic acid centrally in
rats leads to inhibition of food intake and glucose production, while infusion of triglycerides for 24 h leads to
hepatic insulin resistance associated with increased glucose-stimulated insulin secretion and accompanied by
decreased splanchnic sympathetic nerve activity, the latter
effects being dependent on ␤-oxidation of the substrate.
Transient increases in plasma insulin could be induced by
a single intracarotid injection of oleic acid without
changes in plasma glucose, indicating a direct effect of
FFAs on neural control of insulin secretion. These authors
have also provided evidence for the existence of hypothalamic subpopulations of neurones that are either excited
or inhibited by FFAs in vitro, consistent with their role in
S4
central fuel sensing. Thus, central dysregulation of fatty
acid signaling could be a factor leading to impaired
glucoregulation of insulin secretion.
Ahima and coworkers review the central effects of
adipocytokines on metabolism and energy homeostasis,
focusing mainly on leptin and adiponectin. A great deal is
now known about their mechanisms of production, their
various circulating plasma forms, and their putative receptors and signaling pathways. Leptin normally acts to
prevent the negative changes associated with starvation
and weight reduction, including reduced energy expenditure, insulin resistance, hyperlipidemia, and fertility. Central leptin administration in ob/ob mice suppresses hepatic
glucose production followed by food intake and weight
loss, while restoring insulin sensitivity. Both leptin and
adiponectin act peripherally to increase AMP-activated
protein kinase and other enzymes involved in lipid metabolism in liver and muscle, as well as centrally. The mode of
entry of adiponectin into the CNS remains unsettled, but
adiponectin receptors are present in cerebral microvessels. These issues and a variety of other adipocytokines
and putative hormones produced by fat cells remain to be
studied in order to clarify their roles in human metabolic
pathophysiology.
The conference concluded with an excellent personal
overview by Porte of the history and development of our
current concepts regarding the central regulation of energy homeostasis and the key role of insulin in this process
as they have developed during the past 30 years of his
research. He and his colleagues, as well as many others
drawn into this field, have made great strides in elucidating the mechanisms by which insulin and other more
recently discovered hormones/cytokines enter and act in
the brain to regulate and integrate the various organ
systems of the body that must all work harmoniously
together to maintain an optimal normal state. Porte concludes that “the overwhelming evidence that insulin plays
a key dual role in the regulation of carbohydrate metabolism and body weight suggests that further analysis of its
CNS effects will continue to be a fruitful area for study and
potentially therapeutic intervention.”
We are indebted to the Secretary of the IGIS group, Dr.
Alain Ktorza, and to Laurence Alliot’s team at Servier for
their outstanding assistance with the organization of the
Symposium, as well as to Catriona Donagh for the editorial
management of this supplement.
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006