Feature Article/Aronoff et al.
`
`Glucose Metabolism and Regulation:
`Beyond Insulin and Glucagon
`
`Stephen L. Aronoff, MD, FACP, FACE; Kathy Berkowitz, APRN, BC, FNP, CDE; Barb Shreiner, RN,
`MN, CDE, BC-ADM; and Laura Want, RN, MS, CDE, CCRC, BC-ADM
`
`Abstract
`
`Insulin and glucagon are potent regu-
`lators of glucose metabolism. For
`decades, we have viewed diabetes
`from a bi-hormonal perspective of
`glucose regulation. This perspective is
`incomplete and inadequate in explain-
`ing some of the difficulties that
`patients and practitioners face when
`attempting to tightly control blood
`glucose concentrations. Intensively
`managing diabetes with insulin is
`
`fraught with frustration and risk.
`Despite our best efforts, glucose fluc-
`tuations are unpredictable, and hypo-
`glycemia and weight gain are com-
`mon. These challenges may be a result
`of deficiencies or abnormalities in
`other glucoregulatory hormones. New
`understanding of the roles of other
`pancreatic and incretin hormones has
`led to a multi-hormonal view of glu-
`cose homeostasis.
`
`HISTORICAL PERSPECTIVE
`Our understanding of diabetes as a
`metabolic disease has evolved signifi-
`cantly since the discovery of insulin in
`the 1920s. Insulin was identified as a
`potent hormonal regulator of both
`glucose appearance and disappear-
`ance in the circulation. Subsequently,
`diabetes was viewed as a mono-hor-
`monal disorder characterized by
`absolute or relative insulin deficiency.
`Since its discovery, insulin has been
`the only available pharmacological
`treatment for patients with type 1
`diabetes and a mainstay of therapy
`for patients with insulin-deficient
`type 2 diabetes.1–7
`The recent discovery of additional
`hormones with glucoregulatory
`actions has expanded our understand-
`ing of how a variety of different hor-
`mones contribute to glucose home-
`ostasis. In the 1950s, glucagon was
`characterized as a major stimulus of
`hepatic glucose production. This dis-
`covery led to a better understanding
`of the interplay between insulin and
`glucagon, thus leading to a bi-hor-
`monal definition of diabetes.
`Subsequently, the discovery of a sec-
`ond ␤-cell hormone, amylin, was first
`reported in 1987. Amylin was deter-
`mined to have a role that comple-
`mented that of insulin, and, like
`
`Diabetes Spectrum Volume 17, Number 3, 2004
`
`insulin, was found to be deficient in
`people with diabetes. This more
`recent development led to a view of
`glucose homeostasis involving multi-
`ple pancreatic hormones.8
`In the mid 1970s, several gut hor-
`mones were identified. One of these,
`an incretin hormone, glucagon-like
`peptide-1 (GLP-1), was recognized as
`another important contributor to the
`maintenance of glucose homeosta-
`sis.9,10 Based on current understand-
`ing, glucose homeostasis is governed
`by the interplay of insulin, glucagon,
`amylin, and incretin hormones.
`This enhanced understanding of
`glucose homeostasis will be central to
`the design of new pharmacological
`agents to promote better clinical out-
`comes and quality of life for people
`with diabetes. This review will focus
`on the more recently discovered hor-
`mones involved in glucose homeostasis
`and is not intended to be a compre-
`hensive review of diabetes therapies.
`
`NORMAL PHYSIOLOGY
`Plasma glucose concentration is a
`function of the rate of glucose enter-
`ing the circulation (glucose appear-
`ance) balanced by the rate of glucose
`removal from the circulation (glu-
`cose disappearance). Circulating glu-
`cose is derived from three sources:
`
`183
`
`Address correspondence and requests
`for reprints to: Barb Schreiner, RN,
`MN, CDE, BC-ADM, Amylin
`Pharmaceuticals, Inc., 9360 Towne
`Centre Drive, San Diego, CA 92121.
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`Feature Article/Beyond Insulin and Glucagon
`
`intestinal absorption during the fed
`state, glycogenolysis, and gluconeo-
`genesis. The major determinant of
`how quickly glucose appears in the
`circulation during the fed state is the
`rate of gastric emptying. Other
`sources of circulating glucose are
`derived chiefly from hepatic process-
`es: glycogenolysis, the breakdown of
`glycogen, the polymerized storage
`form of glucose; and gluconeogene-
`sis, the formation of glucose primari-
`ly from lactate and amino acids dur-
`ing the fasting state.
`Glycogenolysis and gluconeogene-
`sis are partly under the control of
`glucagon, a hormone produced in the
`␣-cells of the pancreas. During the
`first 8–12 hours of fasting,
`glycogenolysis is the primary mecha-
`nism by which glucose is made avail-
`able (Figure 1A). Glucagon facilitates
`this process and thus promotes glu-
`cose appearance in the circulation.
`Over longer periods of fasting, glu-
`cose, produced by gluconeogenesis, is
`released from the liver.
`Glucoregulatory hormones include
`insulin, glucagon, amylin, GLP-1, glu-
`cose-dependent insulinotropic peptide
`(GIP), epinephrine, cortisol, and
`growth hormone. Of these, insulin
`and amylin are derived from the ␤-
`cells, glucagon from the ␣-cells of the
`pancreas, and GLP-1 and GIP from
`the L-cells of the intestine.
`The glucoregulatory hormones of
`the body are designed to maintain
`circulating glucose concentrations in
`a relatively narrow range. In the fast-
`ing state, glucose leaves the circula-
`tion at a constant rate. To keep pace
`with glucose disappearance, endoge-
`nous glucose production is necessary.
`For all practical purposes, the sole
`source of endogenous glucose pro-
`duction is the liver. Renal gluconeo-
`genesis contributes substantially to
`the systemic glucose pool only during
`periods of extreme starvation.
`Although most tissues have the abili-
`ty to hydrolyze glycogen, only the
`liver and kidneys contain glucose-6-
`phosphatase, the enzyme necessary
`for the release of glucose into the cir-
`culation. In the bi-hormonal model
`of glucose homeostasis, insulin is the
`key regulatory hormone of glucose
`disappearance, and glucagon is a
`major regulator of glucose appear-
`ance. After reaching a post-meal
`peak, blood glucose slowly decreases
`
`Figure 1. Glucose homeostasis: roles of insulin and glucagon. 1A. For nondia-
`betic individuals in the fasting state, plasma glucose is derived from
`glycogenolysis under the direction of glucagon (1). Basal levels of insulin con-
`trol glucose disposal (2). Insulin’s role in suppressing gluconeogenesis and
`glycogenolysis is minimal due to low insulin secretion in the fasting state (3).
`1B. For nondiabetic individuals in the fed state, plasma glucose is derived
`from ingestion of nutrients (1). In the bi-hormonal model, glucagon secretion
`is suppressed through the action of endogenous insulin secretion (2). This
`action is facilitated through the paracrine route (communication within the
`islet cells) (3). Additionally, in the fed state, insulin suppresses gluconeogenesis
`and glycogenolysis in the liver (4) and promotes glucose disposal in the
`periphery (5). 1C. For individuals with diabetes in the fasting state, plasma
`glucose is derived from glycogenolysis and gluconeogenesis (1) under the
`direction of glucagon (2). Exogenous insulin (3) influences the rate of periph-
`eral glucose disappearance (4) and, because of its deficiency in the portal cir-
`culation, does not properly regulate the degree to which hepatic gluconeogene-
`sis and glycogenolysis occur (5). 1D. For individuals with diabetes in the fed
`state, exogenous insulin (1) is ineffective in suppressing glucagon secretion
`through the physiological paracrine route (2), resulting in elevated hepatic glu-
`cose production (3). As a result, the appearance of glucose in the circulation
`exceeds the rate of glucose disappearance (4). The net effect is postprandial
`hyperglycemia (5).
`during the next several hours, even-
`tually returning to fasting levels. In
`the immediate post-feeding state, glu-
`cose removal into skeletal muscle and
`adipose tissue is driven mainly by
`insulin. At the same time, endoge-
`nous glucose production is sup-
`pressed by 1) the direct action of
`insulin, delivered via the portal vein,
`on the liver, and 2) the paracrine
`effect or direct communication with-
`in the pancreas between the ␣- and
`␤-cells, which results in glucagon
`suppression (Figure 1B).11–14
`
`␤-CELL HORMONES
`Insulin
`Until recently, insulin was the only
`pancreatic ␤-cell hormone known to
`lower blood glucose concentrations.
`Insulin, a small protein composed of
`two polypeptide chains containing 51
`amino acids, is a key anabolic hor-
`mone that is secreted in response to
`increased blood glucose and amino
`acids following ingestion of a meal.
`Like many hormones, insulin exerts
`its actions through binding to specific
`receptors present on many cells of the
`
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`
`Table 1. Effects of Primary Glucoregulatory Hormones
`
`PANCREAS
`␣-cells
`Glucagon
`
`␤-cells
`Insulin
`
`• Stimulates the breakdown of stored liver glycogen
`• Promotes hepatic gluconeogenesis
`• Promotes hepatic ketogenesis
`
`• Affects glucose metabolism and storage of ingested nutrients
`• Promotes glucose uptake by cells
`• Suppresses postprandial glucagon secretion
`• Promotes protein and fat synthesis
`• Promotes use of glucose as an energy source
`
`Amylin
`
`• Suppresses postprandial glucagon secretion
`• Slows gastric emptying
`• Reduces food intake and body weight
`
`INTESTINE
`L-cells
`GLP-1
`
`• Enhances glucose-dependent insulin secretion
`• Suppresses postprandial glucagon secretion
`• Slows gastric emptying
`• Reduces food intake and body weight
`• Promotes ␤-cell health
`
`if glucose concentrations remain
`high.13,14
`While glucose is the most potent
`stimulus of insulin, other factors stim-
`ulate insulin secretion. These addition-
`al stimuli include increased plasma
`concentrations of some amino acids,
`especially arginine, leucine, and lysine;
`GLP-1 and GIP released from the gut
`following a meal; and parasympathet-
`ic stimulation via the vagus nerve.16,17
`
`Amylin
`Isolated from pancreatic amyloid
`deposits in the islets of Langerhans,
`amylin was first reported in the litera-
`ture in 1987. Amylin, a 37–amino
`acid peptide, is a neuroendocrine hor-
`mone coexpressed and cosecreted
`with insulin by pancreatic ␤-cells in
`response to nutrient stimuli.8,10,18,19
`When secreted by the pancreas, the
`insulin-to-amylin molar ratio in the
`portal circulation is approximately
`50:1. Because of hepatic extraction of
`insulin, this ratio falls to ~ 20:1 in the
`peripheral circulation.20,21
`Studies in humans have demon-
`strated that the secretory and plasma
`concentration profiles of insulin and
`amylin are similar with low fasting
`concentrations and increases in
`response to nutrient intake.22,23 In
`healthy adults, fasting plasma amylin
`concentrations range from 4 to
`8 pmol/l rising as high as 25 pmol/l
`postprandially. In subjects with dia-
`betes, amylin is deficient in type 1 and
`impaired in type 2 diabetes.24,25
`Preclinical findings indicate that
`amylin works with insulin to help
`coordinate the rate of glucose appear-
`ance and disappearance in the circula-
`tion, thereby preventing an abnormal
`rise in glucose concentrations
`(Figure 2).26
`Amylin complements the effects of
`insulin on circulating glucose concen-
`
`body, including fat, liver, and muscle
`cells. The primary action of insulin is
`to stimulate glucose disappearance.
`Insulin helps control postprandial
`glucose in three ways. Initially,
`insulin signals the cells of insulin-sen-
`sitive peripheral tissues, primarily
`skeletal muscle, to increase their
`uptake of glucose.15 Secondly, insulin
`acts on the liver to promote glycogen-
`esis. Finally, insulin simultaneously
`inhibits glucagon secretion from pan-
`creatic ␣-cells, thus signalling the
`liver to stop producing glucose via
`glycogenolysis and gluconeogenesis
`(Table 1).
`All of these actions reduce blood
`glucose.13 Other actions of insulin
`include the stimulation of fat synthe-
`sis, promotion of triglyceride storage
`in fat cells, promotion of protein syn-
`thesis in the liver and muscle, and
`proliferation of cell growth.13
`Insulin action is carefully regulat-
`ed in response to circulating glucose
`concentrations. Insulin is not secret-
`ed if the blood glucose concentration
`is ≤ 3.3 mmol/l, but is secreted in
`increasing amounts as glucose con-
`centrations increase beyond this
`threshold.14 Postprandially, the
`secretion of insulin occurs in two
`phases: an initial rapid release of
`preformed insulin, followed by
`increased insulin synthesis and
`release in response to blood glucose.
`Long-term release of insulin occurs
`
`Figure 2. Postprandial glucose flux in nondiabetic controls. Postprandial glu-
`cose flux is a balance between glucose appearance in the circulation and glu-
`cose disappearance or uptake. Glucose appearance is a function of hepatic
`(endogenous) glucose production and meal-derived sources and is regulated by
`pancreatic and gut hormones. Glucose disappearance is insulin mediated.
`Calculated from data in the study by Pehling et al.26
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`
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`
`maintains basal blood glucose concen-
`trations within a normal range during
`the fasting state. When plasma glu-
`cose falls below the normal range,
`glucagon secretion increases, resulting
`in hepatic glucose production and
`return of plasma glucose to the nor-
`mal range.39,40 This endogenous
`source of glucose is not needed during
`and immediately following a meal,
`and glucagon secretion is suppressed.
`When coupled with insulin’s direct
`effect on the liver, glucagon suppres-
`sion results in a near-total suppression
`of hepatic glucose output (Figure 4).
`In the diabetic state, there is inade-
`quate suppression of postprandial
`glucagon secretion (hyperglucagone-
`mia)41,42 resulting in elevated hepatic
`glucose production (Figure 4).
`Importantly, exogenously adminis-
`tered insulin is unable both to restore
`normal postprandial insulin concen-
`trations in the portal vein and to sup-
`press glucagon secretion through a
`paracrine effect. This results in an
`abnormally high glucagon-to-insulin
`ratio that favors the release of hepatic
`glucose.43 These limits of exogenously
`administered insulin therapy are well
`documented in individuals with type 1
`or type 2 diabetes and are considered
`to be important contributors to the
`postprandial hyperglycemic state
`characteristic of diabetes.
`
`INCRETIN HORMONES GLP-1
`AND GIP
`The intricacies of glucose homeostasis
`become clearer when considering the
`role of gut peptides. By the late 1960s,
`Perley and Kipnis44 and others demon-
`strated that ingested food caused a
`more potent release of insulin than
`glucose infused intravenously. This
`effect, termed the “incretin effect,”
`suggested that signals from the gut are
`important in the hormonal regulation
`of glucose disappearance.
`Additionally, these hormonal signals
`from the proximal gut seemed to help
`regulate gastric emptying and gut
`motility.
`Several incretin hormones have
`been characterized, and the dominant
`ones for glucose homeostasis are GIP
`and GLP-1. GIP stimulates insulin
`secretion and regulates fat metabo-
`lism, but does not inhibit glucagon
`secretion or gastric emptying.45 GIP
`levels are normal or slightly elevated
`in people with type 2 diabetes.46
`
`Figure 3. Glucose homeostasis: roles of insulin, glucagon, amylin, and GLP-1.
`The multi-hormonal model of glucose homeostasis (nondiabetic individuals):
`in the fed state, amylin communicates through neural pathways (1) to suppress
`postprandial glucagon secretion (2) while helping to slow the rate of gastric
`emptying (3). These actions regulate the rate of glucose appearance in the cir-
`culation (4). *In animal models, amylin has been shown to dose-dependently
`reduced food intake and body weight (5). In addition, incretin hormones, such
`as GLP-1, glucose-dependently enhance insulin secretion (6) and suppress
`glucagon secretion (2) and, via neural pathways, help slow gastric emptying
`and reduce food intake and body weight (5).
`trations via two main mechanisms
`plasma glucose concentrations as well
`(Figure 3). Amylin suppresses post-
`as circulating peptides, including
`prandial glucagon secretion,27 thereby
`amylin.33–36
`decreasing glucagon-stimulated hepatic
`In summary, amylin works to regu-
`glucose output following nutrient
`late the rate of glucose appearance
`ingestion. This suppression of post-
`from both endogenous (liver-derived)
`prandial glucagon secretion is postulat-
`and exogenous (meal-derived)
`ed to be centrally mediated via efferent
`sources, and insulin regulates the rate
`vagal signals. Importantly, amylin does
`of glucose disappearance.37
`not suppress glucagon secretion during
`α-CELL HORMONE: GLUCAGON
`insulin-induced hypoglycemia.21,28
`Glucagon is a key catabolic hormone
`Amylin also slows the rate of gastric
`consisting of 29 amino acids. It is
`emptying and, thus, the rate at which
`secreted from pancreatic ␣-cells.
`nutrients are delivered from the stom-
`Described by Roger Unger in the
`ach to the small intestine for absorp-
`1950s, glucagon was characterized as
`tion.29 In addition to its effects on
`opposing the effects of insulin.38
`glucagon secretion and the rate of gas-
`tric emptying, amylin dose-dependently
`Glucagon plays a major role in sus-
`reduces food intake and body weight in
`taining plasma glucose during fasting
`animal models (Table 1).30–32
`conditions by stimulating hepatic glu-
`cose production.
`Amylin exerts its actions primarily
`Unger was the first to describe the
`through the central nervous system.
`diabetic state as a “bi-hormonal” dis-
`Animal studies have identified specific
`ease characterized by insulin deficien-
`calcitonin-like receptor sites for
`cy and glucagon excess. He further
`amylin in regions of the brain, pre-
`speculated that a therapy targeting the
`dominantly in the area postrema. The
`correction of glucagon excess would
`area postrema is a part of the dorsal
`offer an important advancement in
`vagal complex of the brain stem. A
`the treatment of diabetes.38
`notable feature of the area postrema is
`that it lacks a blood-brain barrier,
`Hepatic glucose production, which
`allowing exposure to rapid changes in
`is primarily regulated by glucagon,
`
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`DIABETES PATHOPHYSIOLOGY
`Our understanding of the pathophysi-
`ology of diabetes is evolving. Type 1
`diabetes has been characterized as an
`autoimmune-mediated destruction of
`pancreatic ␤-cells.60 The resulting defi-
`ciency in insulin also means a deficien-
`cy in the other cosecreted and colocat-
`ed ␤-cell hormone, amylin.25 As a
`result, postprandial glucose concen-
`trations rise due to lack of insulin-
`stimulated glucose disappearance,
`poorly regulated hepatic glucose pro-
`duction, and increased or abnormal
`gastric emptying following a meal.61
`Early in the course of type 2 dia-
`betes, postprandial ␤-cell action
`becomes abnormal, as evidenced by
`the loss of immediate insulin response
`to a meal.62 Peripheral insulin resis-
`tance coupled with progressive ␤-cell
`failure and decreased availability of
`insulin, amylin, and GLP-163 con-
`tribute to the clinical picture of hyper-
`glycemia in diabetes.
`Abnormal gastric emptying is com-
`mon to both type 1 and type 2 dia-
`betes. The rate of gastric emptying is a
`key determinant of postprandial glu-
`cose concentrations (Figure 5).64 If
`gastric emptying is accelerated, then
`the presentation of meal-derived glu-
`cose to the circulation is poorly timed
`with insulin delivery. In individuals
`with diabetes, the absent or delayed
`secretion of insulin further exacer-
`bates postprandial hyperglycemia.
`Both amylin and GLP-1 regulate gas-
`tric emptying by slowing the delivery
`of nutrients from the stomach to the
`small intestine.
`
`REPLACEMENT OF INSULIN
`For the past 80 years, insulin has been
`the only pharmacological alternative,
`but it has replaced only one of the hor-
`monal compounds required for glu-
`cose homeostasis. Newer formulations
`of insulin and insulin secretagogues,
`such as sulfonylureas and meglitinides,
`have facilitated improvements in
`glycemic control. While sulfonylureas
`and meglitinides have been used to
`directly stimulate pancreatic ␤-cells to
`secrete insulin, insulin replacement still
`has been the cornerstone of treatment
`for type 1 and advanced type 2 dia-
`betes for decades. Advances in insulin
`therapy have included not only
`improving the source and purity of the
`hormone, but also developing more
`physiological means of delivery.
`
`Figure 4. Insulin and glucagon secretion: nondiabetic and diabetic subjects. In
`nondiabetic subjects (left panel), glucose-stimulated insulin and amylin release
`from the ␤-cells results in suppression of postprandial glucagon secretion. In a
`subject with type 1 diabetes, infused insulin does not suppress ␣-cell produc-
`tion of glucagon. Adapted from Ref. 38.
`While GIP is a more potent incretin
`hormone, GLP-1 is secreted in greater
`concentrations and is more physiolog-
`ically relevant in humans.47
`GLP-1 also stimulates glucose-
`dependent insulin secretion but is sig-
`nificantly reduced postprandially in
`people with type 2 diabetes or
`impaired glucose tolerance.46,48 GLP-1
`stimulates insulin secretion when plas-
`ma glucose concentrations are high
`but not when plasma glucose concen-
`trations approach or fall below the
`normal range. Derived from the
`proglucagon molecule in the intestine,
`GLP-1 is synthesized and secreted by
`the L-cells found mainly in the ileum
`and colon. Circulating GLP-1 concen-
`trations are low in the fasting state.
`However, both GIP and GLP-1 are
`effectively stimulated by ingestion of a
`mixed meal or meals enriched with
`fats and carbohydrates.49,50 In contrast
`to GIP, GLP-1 inhibits glucagon secre-
`tion and slows gastric emptying.51
`GLP-1 has many glucoregulatory
`effects (Table 1 and Figure 3). In the
`pancreas, GLP-1 stimulates insulin
`secretion in a glucose-dependent man-
`ner while inhibiting glucagon secre-
`tion.52,53 Animal studies have demon-
`strated that the action of GLP-1
`occurs directly through activation of
`GLP-1 receptors on the pancreatic ␤-
`cells and indirectly through sensory
`
`nerves.54 GLP-1 has a plasma half-life
`of about 2 minutes, and its disappear-
`ance is regulated primarily by the
`enzyme dipeptidyl peptidase-IV (DPP-
`IV), which rapidly cleaves and inacti-
`vates GLP-1.
`Infusion of GLP-1 lowers postpran-
`dial glucose as well as overnight fast-
`ing blood glucose concentrations.55
`The postprandial effect of GLP-1 is
`partly due to inhibition of glucagon
`secretion. Yet while GLP-1 inhibits
`glucagon secretion in the fed state, it
`does not appear to blunt glucagon’s
`response to hypoglycemia.56 GLP-1
`helps regulate gastric emptying and
`gastric acid secretion,17 perhaps by
`signalling GLP-1 receptors in the
`brain and thereby stimulating efferent
`tracts of the vagus nerve.56 As gastric
`emptying slows, the postprandial glu-
`cose excursion is reduced.
`Administration of GLP-1 has been
`associated with the regulation of feed-
`ing behavior and body weight.57,58 In
`addition, there have been reported
`observations of GLP-1 improving
`insulin sensitivity and enhancing glu-
`cose disposal.58
`Of significant and increasing inter-
`est is the role GLP-1 may have in
`preservation of ␤-cell function and ␤-
`cell proliferation.59 In animal studies,
`GLP-1 has been shown to enhance
`functional ␤-cell mass.59
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`as the role of incretin hormones has
`been elucidated. Incretin hormones
`play a role in helping regulate glucose
`appearance and in enhancing insulin
`secretion. Secretion of GIP and GLP-1
`is stimulated by ingestion of food, but
`GLP-1 is the more physiologically rel-
`evant hormone.71,72
`However, replacing GLP-1 in its
`natural state poses biological chal-
`lenges. In clinical trials, continuous
`subcutaneous or intravenous infusion
`was superior to single or repeated
`injections of GLP-1 because of the
`rapid degradation of GLP-1 by DPP-
`IV.
`To circumvent this intensive and
`expensive mode of treatment, clinical
`development of compounds that elicit
`similar glucoregulatory effects to
`those of GLP-1 are being investigated.
`These compounds, termed incretin
`mimetics, have a longer duration of
`action than native GLP-1. In addition
`to incretin mimetics, research indi-
`cates that DPP-IV inhibitors may
`improve glucose control by increasing
`the action of native GLP-1. These new
`classes of investigational compounds
`have the potential to enhance insulin
`secretion and suppress prandial
`glucagon secretion in a glucose-depen-
`dent manner, regulate gastric empty-
`ing, and reduce food intake.73 Lastly,
`incretin mimetics may also play a role
`in preservation of ␤-cell function and
`␤-cell proliferation.
`
`SUMMARY
`Despite current advances in pharma-
`cological therapies for diabetes,
`attaining and maintaining optimal
`glycemic control has remained elusive
`and daunting. Intensified management
`clearly has been associated with
`decreased risk of complications.6,74
`Yet, despite this scientific understand-
`ing, the average hemoglobin A1c in
`patients with diabetes in the United
`States is > 9%.75
`Glucose regulation is an exquisite
`orchestration of many hormones,
`both pancreatic and gut, that exert
`effect on multiple target tissues, such
`as muscle, brain, liver, and adipocyte.
`While health care practitioners and
`patients have had multiple therapeutic
`options for the past 10 years, both
`continue to struggle to achieve and
`maintain good glycemic control.
`Currently available therapies do not
`perfectly address many of the abnor-
`
`REGULATION OF GLUCAGON
`ACTION
`Clearly, insulin replacement therapy
`has been an important step toward
`restoration of glucose homeostasis.
`But it is only part of the ultimate solu-
`tion. The vital relationship between
`insulin and glucagon has suggested
`additional areas for treatment. With
`inadequate concentrations of insulin
`and elevated concentrations of
`glucagon in the portal vein,
`glucagon’s actions are excessive, con-
`tributing to an endogenous and
`unnecessary supply of glucose in the
`fed state. To date, no pharmacological
`means of regulating glucagon exist
`and the need to decrease postprandial
`glucagon secretion remains a clinical
`target for future therapies.
`
`Figure 5. Gastric emptying rate is an important determinant of postprandial
`glycemia. In nondiabetic subjects (n = 16), plasma glucose concentration
`increases as the rate of gastric emptying increases (r = 0.58, P < 0.05). Adapted
`from Ref. 64.
`Clearly, there are limitations that
`hinder normalizing blood glucose
`using insulin alone. First, exogenous-
`ly administered insulin does not
`mimic endogenous insulin secretion.
`In normal physiology, the liver is
`exposed to a two- to fourfold
`increase in insulin concentration
`compared to the peripheral circula-
`tion.65 Peripherally injected insulin
`does not approach this ratio, thus
`resulting in inadequate hepatic glu-
`cose suppression.66–68 Second,
`insulin’s paracrine suppression of
`glucagon is limited in diabetes and
`inadequately compensated for by
`peripherally delivered insulin
`(Figures 1C, 1D). In the postprandial
`state, when glucagon concentrations
`should be low and glycogen stores
`should be rebuilt, there is a paradox-
`ical elevation of glucagon and deple-
`tion of glycogen stores.69 And final-
`ly, therapeutically increasing insulin
`doses results in further peripheral
`hyperinsulinemia, which may predis-
`pose the individual to hypoglycemia
`and weight gain. As demonstrated in
`the Diabetes Control and
`Complications Trial and the United
`Kingdom Prospective Diabetes
`Study, intensified care is not without
`risk. In both studies, those subjects
`in the intensive therapy groups expe-
`rienced a two- to threefold increase
`in severe hypoglycemia.4,6
`Additionally, intensification of dia-
`betes management was associated
`with weight gain.70
`
`AMYLIN ACTIONS
`It is now evident that glucose appear-
`ance in the circulation is central to
`glucose homeostasis, and this aspect is
`not addressed with exogenously
`administered insulin. Amylin works
`with insulin and suppresses glucagon
`secretion. It also helps regulate gastric
`emptying, which in turn influences the
`rate of glucose appearance in the cir-
`culation. A synthetic analog of human
`amylin that binds to the amylin recep-
`tor, an amylinomimetic agent, is in
`development.
`
`GLP-1 ACTIONS
`The picture of glucose homeostasis
`has become clearer and more complex
`
`188
`
`Diabetes Spectrum Volume 17, Number 3, 2004
`
`Boehringer Ex. 2006
`Mylan v. Boehringer Ingelheim
`IPR2016-01563
`Page 6
`
`

`
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`There remains a need for new
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`current therapeutic armamentarium
`without some of their clinical short-
`comings such as the risk of hypo-
`glycemia and weight gain. These
`evolving therapies offer the potential
`for more effective management of dia-
`betes from a multi-hormonal perspec-
`tive (Figure 3) and are now under
`clinical development.
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