Insulin and glucagon are potent regulators of glucose metabolism. For decades, we have viewed diabetes from a bi-hormonal perspective of glucose regulation. This perspective is incomplete and inadequate in explaining 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 fluctuations are unpredictable, and hypoglycemia and weight gain are common. 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 glucose homeostasis.

Our understanding of diabetes as a metabolic disease has evolved significantly since the discovery of insulin in the 1920s. Insulin was identified as a potent hormonal regulator of both glucose appearance and disappearance in the circulation. Subsequently, diabetes was viewed as a mono-hormonal 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.17 

The recent discovery of additional hormones with glucoregulatory actions has expanded our understanding of how a variety of different hormones contribute to glucose homeostasis. In the 1950s, glucagon was characterized as a major stimulus of hepatic glucose production. This discovery led to a better understanding of the interplay between insulin and glucagon, thus leading to a bi-hormonal definition of diabetes. Subsequently, the discovery of a secondβ-cell hormone, amylin, was first reported in 1987. Amylin was determined to have a role that complemented that of insulin, and, like insulin, was found to be deficient in people with diabetes. This more recent development led to a view of glucose homeostasis involving multiple pancreatic hormones.8 

In the mid 1970s, several gut hormones 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 homeostasis.9,10 Based on current understanding, 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 outcomes and quality of life for people with diabetes. This review will focus on the more recently discovered hormones involved in glucose homeostasis and is not intended to be a comprehensive review of diabetes therapies.

Plasma glucose concentration is a function of the rate of glucose entering the circulation (glucose appearance) balanced by the rate of glucose removal from the circulation (glucose disappearance). Circulating glucose is derived from three sources: intestinal absorption during the fed state,glycogenolysis, and gluconeogenesis. 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 processes: glycogenolysis, the breakdown of glycogen, the polymerized storage form of glucose; and gluconeogenesis, the formation of glucose primarily from lactate and amino acids during the fasting state.

Glycogenolysis and gluconeogenesis are partly under the control of glucagon, a hormone produced in the α-cells of the pancreas. During the first 8–12 hours of fasting, glycogenolysis is the primary mechanism by which glucose is made available (Figure 1A). Glucagon facilitates this process and thus promotes glucose appearance in the circulation. Over longer periods of fasting, glucose,produced by gluconeogenesis, is released from the liver.

Glucoregulatory hormones include insulin, glucagon, amylin, GLP-1,glucose-dependent insulinotropic peptide (GIP), epinephrine, cortisol, and growth hormone. Of these, insulin and amylin are derived from theβ-cells, glucagon from the α-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 fasting state, glucose leaves the circulation at a constant rate. To keep pace with glucose disappearance, endogenous glucose production is necessary. For all practical purposes, the sole source of endogenous glucose production is the liver. Renal gluconeogenesis contributes substantially to the systemic glucose pool only during periods of extreme starvation. Although most tissues have the ability to hydrolyze glycogen, only the liver and kidneys contain glucose-6-phosphatase, the enzyme necessary for the release of glucose into the circulation. 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 appearance. After reaching a post-meal peak, blood glucose slowly decreases during the next several hours, eventually returning to fasting levels. In the immediate post-feeding state, glucose removal into skeletal muscle and adipose tissue is driven mainly by insulin. At the same time, endogenous glucose production is suppressed by 1) the direct action of insulin, delivered via the portal vein, on the liver, and 2) the paracrine effect or direct communication within the pancreas between the α- andβ-cells, which results in glucagon suppression(Figure 1B).1114 

Insulin

Until recently, insulin was the only pancreatic β-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 hormone 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 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-sensitive peripheral tissues, primarily skeletal muscle, to increase their uptake of glucose.15 Secondly, insulin acts on the liver to promote glycogenesis. Finally, insulin simultaneously inhibits glucagon secretion from pancreatic α-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 synthesis, promotion of triglyceride storage in fat cells, promotion of protein synthesis in the liver and muscle, and proliferation of cell growth.13 

Insulin action is carefully regulated in response to circulating glucose concentrations. Insulin is not secreted if the blood glucose concentration is≤ 3.3 mmol/l, but is secreted in increasing amounts as glucose concentrations 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 if glucose concentrations remain high.13,14 

While glucose is the most potent stimulus of insulin, other factors stimulate insulin secretion. These additional 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 parasympathetic stimulation via the vagus nerve.16,17 

Amylin

Isolated from pancreatic amyloid deposits in the islets of Langerhans,amylin was first reported in the literature in 1987. Amylin, a 37–amino acid peptide, is a neuroendocrine hormone coexpressed and cosecreted with insulin by pancreatic β-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 demonstrated 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 diabetes,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 appearance and disappearance in the circulation, thereby preventing an abnormal rise in glucose concentrations(Figure 2).26 

Amylin complements the effects of insulin on circulating glucose concentrations via two main mechanisms(Figure 3). Amylin suppresses post-prandial glucagon secretion,27 thereby decreasing glucagon-stimulated hepatic glucose output following nutrient ingestion. This suppression of post-prandial glucagon secretion is postulated to be centrally mediated via efferent vagal signals. Importantly,amylin does not suppress glucagon secretion during insulin-induced hypoglycemia.21,28 Amylin also slows the rate of gastric emptying and, thus, the rate at which nutrients are delivered from the stomach to the small intestine for absorption.29  In addition to its effects on glucagon secretion and the rate of gastric emptying, amylin dose-dependently reduces food intake and body weight in animal models (Table 1).3032 

Amylin exerts its actions primarily through the central nervous system. Animal studies have identified specific calcitonin-like receptor sites for amylin in regions of the brain, predominantly in the area postrema. The area postrema is a part of the dorsal vagal complex of the brain stem. A notable feature of the area postrema is that it lacks a blood-brain barrier, allowing exposure to rapid changes in plasma glucose concentrations as well as circulating peptides, including amylin.3336 

In summary, amylin works to regulate the rate of glucose appearance from both endogenous (liver-derived) and exogenous (meal-derived) sources, and insulin regulates the rate of glucose disappearance.37 

Glucagon is a key catabolic hormone consisting of 29 amino acids. It is secreted from pancreatic α-cells. Described by Roger Unger in the 1950s,glucagon was characterized as opposing the effects of insulin.38  Glucagon plays a major role in sustaining plasma glucose during fasting conditions by stimulating hepatic glucose production.

Unger was the first to describe the diabetic state as a“bi-hormonal” disease characterized by insulin deficiency and glucagon excess. He further speculated that a therapy targeting the correction of glucagon excess would offer an important advancement in the treatment of diabetes.38 

Hepatic glucose production, which is primarily regulated by glucagon,maintains basal blood glucose concentrations within a normal range during the fasting state. When plasma glucose falls below the normal range, glucagon secretion increases, resulting in hepatic glucose production and return of plasma glucose to the normal 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 suppression results in a near-total suppression of hepatic glucose output(Figure 4).

In the diabetic state, there is inadequate suppression of postprandial glucagon secretion(hyperglucagonemia)41,42 resulting in elevated hepatic glucose production(Figure 4). Importantly,exogenously administered insulin is unable both to restore normal postprandial insulin concentrations in the portal vein and to suppress 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.

The intricacies of glucose homeostasis become clearer when considering the role of gut peptides. By the late 1960s, Perley and Kipnis44  and others demonstrated 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 metabolism, but does not inhibit glucagon secretion or gastric emptying.45 GIP levels are normal or slightly elevated in people with type 2 diabetes.46  While GIP is a more potent incretin hormone, GLP-1 is secreted in greater concentrations and is more physiologically relevant in humans.47 

GLP-1 also stimulates glucose-dependent insulin secretion but is significantly reduced postprandially in people with type 2 diabetes or impaired glucose tolerance.46,48 GLP-1 stimulates insulin secretion when plasma glucose concentrations are high but not when plasma glucose concentrations 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 concentrations 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 secretion 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 manner while inhibiting glucagon secretion.52,53 Animal studies have demonstrated that the action of GLP-1 occurs directly through activation of GLP-1 receptors on the pancreatic β-cells and indirectly through sensory nerves.54  GLP-1 has a plasma half-life of about 2 minutes, and its disappearance is regulated primarily by the enzyme dipeptidyl peptidase-IV (DPP-IV), which rapidly cleaves and inactivates GLP-1.

Infusion of GLP-1 lowers postprandial glucose as well as overnight fasting 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 glucose excursion is reduced. Administration of GLP-1 has been associated with the regulation of feeding behavior and body weight.57,58 In addition, there have been reported observations of GLP-1 improving insulin sensitivity and enhancing glucose disposal.58 

Of significant and increasing interest is the role GLP-1 may have in preservation of β-cell function and β-cell proliferation.59  In animal studies, GLP-1 has been shown to enhance functional β-cell mass.59 

Our understanding of the pathophysiology of diabetes is evolving. Type 1 diabetes has been characterized as an autoimmune-mediated destruction of pancreaticβ-cells.60  The resulting deficiency in insulin also means a deficiency in the other cosecreted and colocated β-cell hormone,amylin.25  As a result, postprandial glucose concentrations rise due to lack of insulin-stimulated glucose disappearance, poorly regulated hepatic glucose production, and increased or abnormal gastric emptying following a meal.61 

Early in the course of type 2 diabetes, postprandial β-cell action becomes abnormal, as evidenced by the loss of immediate insulin response to a meal.62  Peripheral insulin resistance coupled with progressive β-cell failure and decreased availability of insulin, amylin, and GLP-163  contribute to the clinical picture of hyperglycemia in diabetes.

Abnormal gastric emptying is common to both type 1 and type 2 diabetes. The rate of gastric emptying is a key determinant of postprandial glucose concentrations (Figure 5).64 If gastric emptying is accelerated, then the presentation of meal-derived glucose to the circulation is poorly timed with insulin delivery. In individuals with diabetes, the absent or delayed secretion of insulin further exacerbates postprandial hyperglycemia. Both amylin and GLP-1 regulate gastric emptying by slowing the delivery of nutrients from the stomach to the small intestine.

For the past 80 years, insulin has been the only pharmacological alternative, but it has replaced only one of the hormonal compounds required for glucose 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 β-cells to secrete insulin,insulin replacement still has been the cornerstone of treatment for type 1 and advanced type 2 diabetes 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.

Clearly, there are limitations that hinder normalizing blood glucose using insulin alone. First, exogenously 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 circulation.65 Peripherally injected insulin does not approach this ratio, thus resulting in inadequate hepatic glucose suppression.6668 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 paradoxical elevation of glucagon and depletion of glycogen stores.69  And finally, therapeutically increasing insulin doses results in further peripheral hyperinsulinemia, which may predispose 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 experienced a two- to threefold increase in severe hypoglycemia.4,6 Additionally, intensification of diabetes management was associated with weight gain.70 

Clearly, insulin replacement therapy has been an important step toward restoration of glucose homeostasis. But it is only part of the ultimate solution. 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, contributing 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.

It is now evident that glucose appearance 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 circulation. A synthetic analog of human amylin that binds to the amylin receptor, an amylinomimetic agent, is in development.

The picture of glucose homeostasis has become clearer and more complex 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 relevant hormone.71,72 

However, replacing GLP-1 in its natural state poses biological challenges. 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 indicates 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-dependent manner, regulate gastric emptying, and reduce food intake.73  Lastly,incretin mimetics may also play a role in preservation of β-cell function and β-cell proliferation.

Despite current advances in pharmacological 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 understanding, 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 abnormalities and/or deficiencies of type 1 or type 2 diabetes.

There remains a need for new interventions that complement our current therapeutic armamentarium without some of their clinical short-comings such as the risk of hypoglycemia and weight gain. These evolving therapies offer the potential for more effective management of diabetes from a multi-hormonal perspective (Figure 3) and are now under clinical development.

Stephen L. Aronoff, MD, FACP, FACE, is a partner and clinical endocrinologist at Endocrine Associates of Dallas and director at the Research Institute of Dallas in Dallas, Tex. Kathy Berkowitz, APRN, BC, FNP, CDE, and Barb Schreiner, RN, MN, CDE, BC-ADM, are diabetes clinical liaisons with the Medical Affairs Department at Amylin Pharmaceuticals, Inc., in San Diego,Calif. Laura Want, RN, MS, CDE, CCRC, BC-ADM, is the clinical research coordinator at MedStar Research Institute in Washington, D.C.

Note of disclosure: Dr. Aronoff has received honoraria for speaking engagements from Amylin Pharmaceuticals, Inc., and Eli Lilly and Company and research support from Amylin, Lilly, and Novo Nordisk. Ms. Berkowitz and Ms. Schreiner are employed by Amylin. Ms. Want serves on an advisory panel for, is a stock shareholder in, and has received honoraria for speaking engagements from Amylin and has served as a research coordinator for studies funded by the company. She has also received research support from Lilly, Novo Nordisk, and MannKind Corporation. Amylin Pharmaceuticals, Inc.,is developing synthetic amylin and incretin hormone products, and Mannkind Corporation is developing an inhaled insulin system for the treatment of diabetes.

1.
American Diabetes Association: Clinical Practice Recommendations 2004.
Diabetes Care
27
(Suppl. 1):
S1
–S150,
2004
2.
Hirsch IB: Type 1 diabetes mellitus and the use of flexible insulin regimens.
Am Fam Physician
60
:
2343
–2352, 2355–2356,
1999
3.
Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA: Insulin analogues and their potential in the management of diabetes mellitus.
Diabetologia
42
:
1151
–1167,
1999
4.
DCCT Research Group: Hypoglycemia in the Diabetes Control and Complications Trial.
Diabetes
46
:
271
–286,
1997
5.
DCCT Research Group: Weight gain associated with intensive therapy in the Diabetes Control and Complications Trial.
Diabetes Care
11
:
567
–573,
1988
6.
UKPDS Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes.
Lancet
352
:
837
–853,
1998
7.
Buse JB, Weyer C,Maggs DG: Amylin replacement with pramlintide in type 1 and type 2 diabetes: a physiological approach to overcome barriers with insulin therapy.
Clinical Diabetes
20
:
137
–144,
2002
8.
Moore CX, Cooper GJS: Co-secretion of amylin and insulin from cultured islet beta-cells:modulation by nutrient secretagogues, islet hormones and hypoglycaemic agents.
Biochem Biophys Res Commun
179
:
1
–9,
1991
9.
Naslund E,Bogefors J, Skogar S, Gryback P, Jacobsson H, Holst JJ, Hellstrom PM: GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans.
Am J Physiol
277
:
R910
–R916,
1999
10.
Cooper GJS, Willis AC, Clark A, Turner RD, Sim RB, Reid KB: Purification and characterization of a peptide from amyloid-rich pancreas of type 2 diabetic patients.
Proc Natl Acad Sci U S A
84
:
8628
–8632,
1987
11.
Wallum BJ, Kahn SE, McCulloch DK, Porte D: Insulin secretion in the normal and diabetic human. In
International Textbook of Diabetes Mellitus.
Alberti KGMM, DeFronzo RA, Keen H, Zimmet P, Eds. Chichester, U.K., John Wiley and Sons,
1992
, p.
285
–301
12.
Lefebvre PJ:Glucagon and its family revisited.
Diabetes Care
18
:
715
–730,
1995
13.
Cryer PE: Glucose homeostasis and hypoglycaemia. In
William's Textbook of Endocrinology.
Wilson JD, Foster DW, Eds. Philadelphia, Pa., W.B. Saunders Company,
1992
, p.
1223
–1253
14.
Gerich JE: Control of glycaemia.
Baillieres Best Pract Res Clin Endocrinol Metab
7
:
551
–586,
1993
15.
Gerich JE,Schneider V, Dippe SE, Langlois M, Noacco C, Karam J, Forsham P:Characterization of the glucagon response to hypoglycemia in man.
J Clin Endocrinol Metab
38
:
77
–82,
1974
16.
Holst JJ:Glucagon-like peptide 1: a newly discovered gastrointestinal hormone.
Gastroenterology
107
:
1848
–1855,
1994
17.
Drucker DJ:Minireview: the glucagon-like peptides.
Endocrinology
142
:
521
–527,
2001
18.
Ogawa A, Harris V,McCorkle SK, Unger RH, Luskey KL: Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment.
J Clin Invest
85
:
973
–976,
1990
19.
Koda JE, Fineman M, Rink TJ, Dailey GE, Muchmore DB, Linarelli LG: Amylin concentrations and glucose control.
Lancet
339
:
1179
–1180,
1992
20.
Data on file, Amylin Pharmaceuticals, Inc., San Diego,Calif.
21.
Weyer C, Maggs DG,Young AA, Kolterman OG: Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: a physiological approach toward improved metabolic control.
Curr Pharm Des
7
:
1353
–1373,
2001
22.
Koda JE, Fineman MS, Kolterman OG, Caro JF: 24 hour plasma amylin profiles are elevated in IGT subjects vs. normal controls (Abstract).
Diabetes
44
(Suppl. 1):
238A
,
1995
23.
Fineman MS, Giotta MP, Thompson RG, Kolterman OG, Koda JE: Amylin response following Sustacal ingestion is diminished in type II diabetic patients treated with insulin(Abstract).
Diabetologia
39
(Suppl.1):
A149
,
1996
24.
Young A: Amylin's physiology and its role in diabetes.
Curr Opin Endocrinol Diab
4
:
282
–290,
1997
25.
Kruger DF, Gatcomb PM, Owen SK: Clinical implications of amylin and amylin deficiency.
Diabetes Educ
25
:
389
–397,
1999
26.
Pehling G, Tessari P, Gerich JE, Haymond MW, Service FJ, Rizza RA: Abnormal meal carbohydrate disposition in insulin-dependent diabetes: relative contributions of endogenous glucose production and initial splanchnic uptake and effect of intensive insulin therapy.
J Clin Invest
74
:
985
–991,
1984
27.
Gedulin BR, Rink TJ, Young AA: Dose-response for glucagonostatic effect of amylin in rats.
Metabolism
46
:
67
–70,
1997
28.
Heise T, Heinemann L, Heller S, Weyer C, Wang Y, Strobel S, Kolterman O, Maggs D: Effect of pramlintide on symptom, catecholamine, and glucagon responses to hypoglycemia in healthy subjects.
Metabolism.
In press
29.
Samson M, Szarka LA, Camilleri M, Vella A, Zinsmeister AR, Rizza RA: Pramlintide, an amylin analog, selectively delays gastric emptying: potential role of vagal inhibition.
Am J Physiol
278
:
G946
–G951,
2000
30.
Bhavsar S, Watkins J, Young A: Synergy between amylin and cholecystokinin for inhibition of food intake in mice.
Physiol Behav
64
:
557
–561,
1998
31.
Rushing PA, Hagan MM, Seeley RJ, Lutz TA, Woods SC: Amylin: a novel action in the brain to reduce body weight.
Endocrinology
141
:
850
–853,
2000
32.
Rushing PA, Hagan MM, Seeley RJ, Lutz TA, D'Alessio DA, Air EL, Woods SC: Inhibition of central amylin signaling increases food intake and body adiposity in rats.
Endocrinology
142
:
5035
–5038,
2001
33.
Wimalawansa SJ:Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily.
Crit Revs Neurobiol
11
:
167
–239,
1997
34.
Beeley NRA,Prickett KS: The amylin, CGRP and calcitonin family of peptides.
Expert Opin Therapeut Patents
6
:
555
–567,
1996
35.
Van Rossum D,Menard DP, Fournier A, St Pierre S, Quirion R: Autoradiographic distribution and receptor binding profile of (I-125) Bolton Hunter-rat amylin binding sites in the rat brain.
J Pharmacol Exp Ther
270
:
779
–787,
1994
36.
Beaumont K, Kenney MA, Young AA, Rink TJ: High affinity amylin binding sites in rat brain.
Mol Pharmacol
44
:
493
–497,
1993
37.
Buse JB, Weyer C,Maggs D: Amylin replacement with pramlintide in type 1 and type 2 diabetes: a physiological approach to overcome barriers with insulin therapy.
Clinical Diabetes
20
:
137
–144,
2002
38.
Unger RH: Glucagon physiology and pathophysiology.
N Engl J Med
285
:
443
–449,
1971
39.
Orci L,Malaisse-Lagae F, Amherdt M, Ravazzola M, Weisswange A, Dobbs RD, Perrelet A,Unger R: Cell contacts in human islets of Langerhans.
J Clin Endocrinol Metab
41
:
841
–844,
1975
40.
Gerich J, Davis J,Lorenzi M, Rizza R, Bohannon N, Karam J, Lewis S, Kaplan R, Schultz T, Cryer P: Hormonal mechanisms of recovery from hypoglycemia in man.
Am J Physiol
236
:
E380
–E385,
1979
41.
Cryer PE: Glucose counterregulation in man.
Diabetes
30
:
261
–264,
1981
42.
Dinneen S, Alzaid A, Turk D, Rizza R: Failure of glucagon suppression contributes to postprandial hyperglycemia in IDDM.
Diabetologia
38
:
337
–343,
1995
43.
Baron AD,Schaeffer L, Schragg P, Kolterman OG: Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetes.
Diabetes
36
:
274
–283,
1987
44.
Perley MJ, Kipnis DM: Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects.
J Clin Invest
46
:
1954
–1962,
1967
45.
Yip RG, Wolfe MM:GIP biology and fat metabolism.
Life Sci
66
:
91
–103,
2000
46.
Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ: Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients.
Diabetes
50
:
609
–613,
2001
47.
Nauck MA,Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W: Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.
J Clin Invest
91
:
301
–307,
1993
48.
Lugari R, Dei Cas A, Ugolotti D, Finardi L, Barilli AL, Ognibene C, Luciani A, Zandomeneghi R,Gnudi A: Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes.
Horm Metab Res
34
:
150
–154,
2002
49.
Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R, Goke B: Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients.
Digestion
56
:
117
–126,
1995
50.
Elliott RM, Morgan LM, Trefger JA, Deacon S, Wright J, Marks V: Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post prandial and 24-h secretion patterns.
J Endocrinol
138
:
159
–166,
1993
51.
Matsuyama T,Komatsu R, Namba M, Watanabe N, Itoh H, Tarui S: Glucagon-like peptide-1 (7-36 amide): a potent glucagonostatic and insulinotropic hormone.
Diabetes Res Clin Pract
5
:
281
–284,
1988
52.
Nauck MA, Holst JJ, Willms B, Schmiegel W: Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for type 2 diabetes.
Exp Clin Endocrinol Diabetes
105
:
187
–195,
1997
53.
Perfetti R, Merkel P: Glucagon-like peptide-1: a major regulator of pancreatic beta-cell function.
Eur J Endocrinol
143
:
717
–725,
2000
54.
Burcelin R, Da Costa A, Drucker D, Thorens B: Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor.
Diabetes
50
:
1720
–1728,
2001
55.
Rachman J, Gribble FM, Barrow BA, Levy JC, Buchanan KD, Turner RC: Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36)amide in patients with NIDDM.
Diabetes
45
:
1524
–1530,
1996
56.
Nauck MA,Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, Hufner M, Schmiegel WH:Effects of glucagon-like peptide 1 on counterregulatory hormone responses,cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers.
J Clin Endocrinol Metab
87
:
1239
–1246,
2002
57.
Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM,Lambert PD, Wilding JP, Smith DM, Ghatei MA, Herbert J, Bloom SR: A role for glucagon-like peptide-1 in the central regulation of feeding.
Nature
379
:
69
–72,
1996
58.
Zander M, Madsbad S, Madsen JL, Holst JJ: Effect of 6-week course of glucagon-like peptide 1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study.
Lancet
359
:
824
–830,
2002
59.
Drucker DJ:Glucagon-like peptides: regulation of cell proliferation, differentiation and apoptosis.
Mol Endocrinol
17
:
161
–171,
2003
60.
Atkinson MA,Maclaren NK: The pathogenesis of insulin-dependent diabetes mellitus.
N Engl J Med
331
:
1428
–1436,
1994
61.
Kruger DF, Gatcomb PM, Owen SK: Clinical implications of amylin and amylin deficiency.
Diabetes Educ
25
:
389
–397,
1999
62.
Kahn SE: The importance of the beta cell in the pathogenesis of type 2 diabetes mellitus.
Am J Med
108
:
2S
–8S,
2000
63.
Toft-Nielsen MB,Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, Holst JJ:Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients.
J Clin Endocrinol Metab
86
:
3717
–3723,
2001
64.
Horowitz M,Edelbroek MA, Wishart JM, Straathof JW: Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects.
Diabetologia
36
:
857
–862,
1993
65.
Zinman B, Tsui EYL: Alternative routes for insulin delivery. In
International Textbook of Diabetes Mellitus.
2nd ed. Alberti KGMM, Zimmet P,Defronzo RA, Eds. New York, John Wiley and Sons,
1997
, p.
929
–936
66.
Jacobs MA, Keulen ET, Kanc K, Casteleijn S, Scheffer P, Deville W, Heine RJ: Metabolic efficacy of preprandial administration of Lys(B28), Pro(B29) human insulin analog in IDDM patients: a comparison with human regular insulin during a three-meal test period.
Diabetes Care
20
:
1279
–1286,
1997
67.
Heinemann L, Heise T, Wahl LC, Trautmann ME, Ampudia J, Starke AA, Berger M: Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: using the rapid acting insulin analogue.
Diabet Med
13
:
625
–629,
1996
68.
Bruttomesso D,Pianta A, Mari A, Valerio A, Marescotti MC, Avogaro A, Tiengo A, Del Prato S:Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients.
Diabetes
48
:
99
–105,
1999
69.
Jiang G, Zhang BB:Glucagon and regulation of glucose metabolism.
Am J Physiol Endocrinol Metab
284
:
E671
–E678,
2003
70.
Purnell JQ,Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD: Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT.
JAMA
280
:
140
–146,
1998
71.
Kreymann B,Williams G, Ghatei MA, Bloom SR: Glucagon-like peptied-1 7-36: physiological incretin in man.
Lancet
2
:
1300
–1303,
1987
72.
Holst JJ:Glucagonlike peptide 1: a newly discovered gastrointestinal hormone.
Gastroenterology
107
:
1848
–1855,
1994
73.
Drucker D:Enhancing incretin action for the treatment of type 2 diabetes.
Diabetes Care
26
:
2929
–2940,
2003
74.
DCCT Research Group: The effect of intensive therapy of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus.
N Engl J Med
329
:
977
–986,
1993
75.
Klein R, Klein BE,Moss SE, Cruickshanks KJ: The medical management of hyperglycemia over a 10-year period in people with diabetes.
Diabetes Care
19
:
744
–750,
1996