Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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glucose administered intravenously. This ability of

the gut to stimulate insulin secretion has been termed

the enteroinsular axis. Gut peptides potentiate insulin

secretin via both neural and endocrine pathways but,

in humans, the endocrine role of the gut hormones

(collectively termed incretins) is considered to be

quantitatively the more important. Although most

members of the secretion family of gut hormones

have the ability to stimulate insulin in pharmaco-

logical doses, only GIP and GLP-1 are both secreted

in response to glucose ingestion and stimulate insulin

secretion at physiological levels. Together they

account for the entire endocrine arm of the entero-

insular axis.

0016 GIP and GLP-1 are both potent stimulators of

glucose-induced insulin secretion. On a molar basis,

GLP-1 is the stronger stimulator, but as it circulates

at lower concentrations than GIP, the contribution

of the two hormones to the enteroinsular axis are

approximately equivalent. These hormones only

stimulate insulin secretion in the presence of hyper-

glycemia. This can be looked upon as providing a

safeguard against inappropriate insulin secretion, as

both hormones are also stimulated by oral fat, when

insulin secretion would be undesirable unless its

hypoglycemic properties were counteracted by simul-

taneous ingestion of carbohydrate.

0017 The neural arm of the enteroinsular axis is more

poorly defined. Both CCK- and VIP-containing

neurons have been implicated as neurotransmitters

stimulating insulin secretion. The smaller forms of

CCK (CCK-4 and CCK-8) also appear to be biologic-

ally active, although their precise role in insulin

stimulation is not yet fully known.

0018 Consistent with the anabolic role that gut hor-

mones play in carbohydrate metabolism, by stimulat-

ing insulin secretion, is a parallel anabolic role in lipid

metabolism. GIP has been shown to have an anabolic

effect on lipid metabolism, stimulating lipoprotein

lipase and enhancing postprandial triglyceride clear-

ance from the plasma. GIP and GLP-1 have also been

shown to stimulate de novo fatty acid synthesis in

adipose tissue. These two GI hormones, which po-

tentiate the secretion of insulin, also exhibit insulin-

like actions systemically and provide a direct link

between the absorption and subsequent metabolic

fate of ingested nutrients.

Appetite Regulation

0019 The regulation of hunger and satiety is a complex

process, involving the interaction of both physio-

logical and psychological factors. There is good ex-

perimental evidence for the involvement of several of

the gut hormones in the short-term regulation of

appetite, although the precise mechanisms whereby

they exert their effects in human appetite control are

less clear. CCK and GLP-1 have been found to medi-

ate satiety in both animal and human studies. The

inhibitory effects of CCK on food intake are stimu-

lated by fat ingestion, and appear to be mediated by a

local gastrointestinal action, although CCK is par-

tially dependent upon an intact vagal nerve supply

in order to exert its satiety effects. Peripheral adminis-

tration of GLP-1 has been shown to suppress appetite

in most, if not all human studies; circulating GLP-1

can theoretically pass the blood–brain barrier to act

centrally. Neuropeptide Y is distributed in the central

nervous system as well as within the gut. It acts in the

brain upon appetite centers in the hypothalamus to

stimulate food intake, and it may also be implicated

in the regulation of leptin, the peptide secreted from

adipose tissue which is involved with the longer-term

mediation of satiety.

Regulation of Secretion

0020Ingestion and absorption of food are the major stim-

uli to gut hormone secretion, especially the endocrine

gut hormones. The major nutrient stimuli for these

hormones are listed in Table 3. The type of nutrient

that stimulates the secretion of an individual gut hor-

mone usually relates to its physiological role. GIP and

GLP-1, for example, the potentiators of insulin secre-

tion, are stimulated by carbohydrate, which in itself

stimulates insulin secretion by raising circulating glu-

cose levels. Fat ingestion is a major stimulus to secre-

tin and CCK whose primary function is concerned

with stimulating pancreatic and biliary secretion,

thus aiding the digestion of fat. GIP secretion is also

stimulated by fat absorption, consistent with the role

of GIP in aiding the clearance of circulating lipids

after a meal, and aiding their uptake into adipose

tissue. The secretory response of a gut hormone to

nutrients is a very precise one. For example, carbohy-

drate-induced GIP secretion is stimulated specifically

by the absorption of actively transported sugars such

as glucose and galactose. The mere presence of nutri-

ents in the gut lumen is insufficient to stimulate GIP

secretion, and sugars such as fructose, whose absorp-

tion does not require active transport mechanism, do

not stimulate GIP secretion. In contrast, GLP-1 secre-

tion is not dependent upon the absorption of nutri-

ents, a property which is consistent with its role as a

regulator of gastric emptying and the smooth delivery

of nutrients to the upper part of the gut. Chronic

dietary changes can also affect gut hormone secre-

tion; a high-fat diet, for example, has been shown to

increase GIP secretion in response to both carbohy-

drate and fat ingestion.

HORMONES/Gut Hormones 3149

0021 Interactions between the various gut hormones

play an important part in the regulation of gut

hormone secretion, particularly in an inhibitory

capacity (Table 3). Thus somatostatin is a physio-

logical paracrine inhibitor of gastrin secretion and

probably plays an endocrine role in the regulation of

other gut hormones, e.g., secretin and neurotensin.

GRP is so named because of its role in the stimulation

of gastric secretion. GRP infusion will also cause

increased plasma concentrations of many other GI

hormones, although the physiological relevance of

this is unclear.

0022 Less is known about the regulation of gut neuro-

peptide secretion. These peptides are synthesized by

intramural neurons and released from nerve terminals

by physiologically appropriate stimuli (e.g., chemical

or mechanically induced reflexes). Vagal stimulation

has been implicated in the release of several gut

neurotransmitter peptides, e.g., VIP and GRP, but its

regulatory role has yet to be fully defined.

See also: Diabetes Mellitus: Etiology; Hormones:

Pancreatic Hormones

Further Reading

Holst JJ, Fahenkrug J, Stadil F and Rehfeld JF (1996) Gas-

trointestinal endocrinology. Scandinavian Journal of

Gastroenterology 216: 27–38.

Morgan LM (1998) The role of gastrointestinal hormones

in carbohydrate and lipid metabolism and homeostasis:

effects of gastric inhibitory polypeptide and glucagon-

like peptide-1. Biochemical Society Transactions 26:

216–222.

Rehfeld JF (1998) The new biology of the gastrointestinal

hormones. Physiological Reviews 78: 1087–1103.

Schultz H, Makhlouf GM and Rauner BB (eds) (1989) The

gastrointestinal system. Neural and endocrine biology.

In: Handbook of Physiology, vol. II, Section 6. Bethesda:

American Physiological Society.

Wilding JPH, Ghatei MA and Bloom SR (1995) Hormones

of the gastrointestinal tract. In: DeGroot LJ (ed.)

Endocrinology, pp. 2870–2894. Philadelpia, London:

Saunders.

Pancreatic Hormones

N H McClenaghan and P R Flatt, University of Ulster,

Coleraine, UK

Pancreatic Secretions

0001The pancreas is a secretory gland playing a key

role in the metabolism of carbohydrates, proteins,

and lipids. Cells of the exocrine pancreas (acini)

secrete pancreatic juice into the duodenum, which

contains enzymes for the digestion of major food

tbl0003 Table 3 Nutritional and other regulation of endocrine gastraintestinal hormone secretion

Hormone/peptide Majornutritional stimulants Other modulators of secretion

Secretin Fat. Exit of meal from stomach causing

duodenal acidification

Stimulation: bile salts

Inhibition: somatostatin

Gastric-inhibitory peptide (GIP) Fat, carbohydrate. Absorption from upper

small intestine

Inhibition: insulin

Glucagon-like peptides Carbohydrate, fat. Presence of food in upper

small intestine

Stimulation: gastrin-releasing peptide (GRP)

Inhibition: somatostatin

Gastrin Amino acids and protein in stomach lumen;

meal-induced gastric distension

Stimulation: GRP, acetylcholine,

norepinephrine (noradrenaline)

Inhibition: acid (pH<3), GIP, secretin, GLP-1,

somatostatin

Chdecystokinin Fat (hydrolysis of triglyceride), phenylalanine

and tryptophan

Stimulation: GRP

Inhibition: trypsin, bile salts, somatostatin

Pancreatic polypeptide Ingestion of meal, especially carbohydrate Stimulation: GRP, motilin, vagal stimulation

Inhibition: somatostatin

Peptide YY Ingestion of meal, especially fat Inhibition: GLP-1

Somatostatin Ingestion of meal, especially fat and protein.

Meal-induced lowering of gastric pH

Stimulation: GIP, CCK, secretin

Inhibition: opioid peptides

Neurotensin Fat ingestion Stimulation: GRP

Inhibition: somatostatin

Motilin Stimulated by both oral and intravenous fat

(inhibited by glucose, amino acids)

Stimulation: duodenal acidification

Inhibition: secretin, GRP, somatostatin

GLP-1, glucagon-like peptide 1.

3150 HORMONES/Pancreatic Hormones

components. The endocrine pancreas synthesizes

and secretes peptide hormones into the blood,

thereby controlling nutrient homeostasis by deter-

mining the metabolic fate of absorbed glucose,

amino acids, and fatty acids, and their mobilization

in times of need from body stores. The following

sections focus specifically on the endocrine pancreas,

and the synthesis, secretion, and action of pancreatic

hormones.

Organization of the Endocrine Pancreas

0002 The endocrine function of the pancreas resides within

the islet of Langerhans, which constitute 1–3% of

total pancreatic mass. The normal adult pancreas

contains about 1 10

pancreatic islets scattered

throughout the body of this elongated organ. Islets

are spherical structures less than the size of a pinhead,

each comprising a cluster of 2000–6000 individual

islet cells surrounded by a connective tissue capsule.

The diameter of the islet ranges from 20 to 300 mm,

depending on cellular composition.

Pancreatic Islet Cells

0003 Pancreatic islets consist of four major types of secre-

tory cell producing insulin (b cells), glucagon (a

cells), somatostatin (a

cells; also referred to as d

cells) and pancreatic polypeptide (PP cells) (Table 1).

These are sometimes also referred to as B, A, and D

cells, respectively. The products of several other

minor secretory cell types located in the islets remain

unknown. Islets also contain small amounts of add-

itional peptides colocalized with classical islet hor-

mones or present in nerve fibers. These agents have

various effects on insulin secretion, as indicated in

Table 1.

0004 Each islet is composed of 60–70% b cells located

primarily as a central core surrounded by an outer

mantle of a

cells (5–25%), a

cells (5–10%) and PP

cells (15–20%). The proportion of a

and PP cells

varies considerably, depending on islet embryonic

origin and location in the pancreas. Islets distributed

the tail and body of the pancreas are generally rich in

cells and contain relatively few PP cells, whereas

the converse applies for islets located the ventral head

region of the pancreas.

Islet Vasculature

0005 Islets are well vascularized and receive a considerable

flow of blood from afferent arterioles arising from the

splenic and pancreaticoduodenal arteries. Within the

islet, the afferent vessels appear to perforate the cellu-

lar mantle, supplying a dense network of capillaries

that traverse the b cell core, before draining into a

small number of venules that ultimately feed into the

pancreatic vein. The vasculature of individual islets is

believed to constitute a tiny intraislet ‘portal’ system,

with blood flowing progressively past b, a

, and a

cells. This arrangement provides effective delivery to

islet cells of bloodborne stimuli, such as glucose, and

ensures rapid circulation of the secreted islet hor-

mones to peripheral sites of action. There is also

recent evidence that elevation of blood glucose spe-

cifically increases islet blood flow, via a cholinergic

mechanism.

Islet Innervation

0006Islets receive an abundant supply of cholinergic, adre-

nergic, and peptidergic (nonadrenergic, noncholiner-

gic (NANC)) nerves that innervate islet cells and the

surrounding capillaries. In addition to the classical

neurotransmitters – acetylcholine and noradrenaline

– the islets contain a number of neuropeptides that

exert stimulatory or inhibitory effects on islet cell

secretions (Tables 1 and 2). Parasympathetic innerv-

ation is activated by feeding, whereas sympathetic

nerves are activated in situations of need such as

starvation or fright.

Islet Cell Interactions

0007Glucagon stimulates the secretion of insulin and

somatostatin, whereas both insulin and somatostatin

tbl0001Table 1 Hormones, peptides colocalized in hormone-

producing cells and neurotransmitters in islets of Langerhans

Cell type Effect oninsulin

secretion

Hormones

Insulin b cells #

Glucagon a

cells "

Somatostatin a

cells #

Pancreatic polypeptide PP cells #

Peptides colocalized

DBI a

, a

cells #

IAPP b cells #

Pancreastatin a

, b, a

cells #

TRH a

, b cells "

Neurotransmitters

Acetylcholine Nerve fibers "

Noradrenaline Nerve fibers #

CCK Nerve fibers "

Galanin Nerve fibers #

GRP Nerve fibers "

VIP Nerve fibers "

", stimulatory effect; #, inhibitory effect; CCK, cholecystokinin;

DBI, diazepam-binding inhibitor; GRP, gastrin-releasing polypeptide;

IAPP, islet amyloid polypeptide; TRH, thyrotropin-releasing hormone;

VIP, vasoactive intestinal polypeptide.

HORMONES/Pancreatic Hormones 3151

are general inhibitors of islet hormone secretions

(Table 2). This provides the basis for the possible

involvement cellular interactions in the integration

of islet secretory function (Figure 1). Such inter-

actions may be restricted to adjacent cells within the

islet, termed paracrine interactions, or may be more

widely mediated through the intraislet portal system,

which delivers insulin from b cells downstream to

cells, followed by onward passage of both insulin

and secreted glucagon to the somatostatin-containing

cells.

Hormone Biosynthesis and Secretion

0008Biosynthesis and secretion of islet hormones occur

through a similar sequence, involving the production

of a precursor polypeptide in the rough endoplasmic

reticulum followed by posttranslational enzymatic

conversion to the active hormone. The active hor-

mone is stored in secretory granules before ultimate

release from the stimulated cell by a regulated process

termed ‘exocytosis.’ This involves movement, aided

by microtubules and microfilaments of the granule to

cell

(glucagon)

β cell

(insulin)

cell

(somatostatin)

(−)

(−) (−)

(−)

(+)

fig0001 Figure 1 Hormonal interactions of major islet cells. Blood flows from b to a

to a

cells draining into the portal vein.

tbl0002 Table 2 Control of insulin, glucagon, somatostatin, and pancreatic polypeptide secretion

Agent Insulin Glucagon Somatostatin Pancreatic polypeptide

Nutrients

Glucose "# " #

Amino acids "" " "

Fatty acids "# " "

Pancreatic hormones

Insulin ## # "

Glucagon " ? " –

Somatostatin ## # #

Pancreatic polypeptide # – # ?

Intestinal hormones

CCK

"" " "

Gastrin "" " –

GIP "" " "

GLP-1[7-36]-amide "# " ?

Secretin "# " –

VIP

"" ? "

Neurotransmitters

Acetylcholine "" # "

-Adrenergic agonists ## # #

b-Adrenergic agonists "" " "

Also present in nerve fibers innervating islet cells.

", stimulatory effect; #, inhibitory effect; – no effect; ?, not established; CCK, cholecystokinin; GIP, gastric inhibitory polypeptide; GLP-1[7-36]-amide,

glucagon-like peptide 1[7-36]amide (sometimes referred to as ‘insulinoptropin’); VIP, vasoactive intestinal polypeptide.

3152 HORMONES/Pancreatic Hormones

the periphery, followed by fusion of the granule mem-

brane with the plasma membrane and liberation of

the granule contents into the blood.

0009 More specific details of events concerning biosyn-

thesis and secretion are best known for insulin. In the

b cell, transcription of messenger ribonucleic acid

(mRNA) gives rise to production of preproinsulin,

an 11.5-kDa polypeptide. This is rapidly cleaved

within 1 min by proteolytic enzymes to proinsulin

(86 amino acid residues, 9 kDa) which is transported

by microvesicles to the Golgi apparatus. Proinsulin is

then packaged into secretory granules, where it is

converted by proteases to equimolar amounts of

insulin (51 residues, 6 kDa) and proinsulin C-peptide.

A number of second messengers are involved in

coupling stimulus recognition to the secretion of

insulin by exocytosis. These include cytoplasmic

calcium ion concentration ([Ca

2þ

]

), cyclic adenosine

monophosphate (cAMP), diacylglycerol (DAG), and

inositol 1,4,5-trisphosphate (IP

0010 In pancreatic a

cells, the initial product of the

proglucagon is a 160-residue polypeptide (18 kDa)

that contains the amino acid sequences of several

biologically active peptides in addition to glucagon.

Posttranslational processing of proglucagon yields

glucagon (29 residues, 3.5 kDa) as the main product,

plus a proglucagon fragment and, possibly, small

amounts of glicentin-related pancreatic peptide

(GRPP). In pancreatic a

cells, preprosomatostatin

(116 residues) is similarly processed to prosomato-

statin (92 residues) before conversion to the active,

14-amino-acid form of somatostatin (SRIF-14,

1.5 kDa). In PP cells, pancreatic polypeptide (36 resi-

dues, 4.3 kDa) also appears to be produced from a

larger, 95-amino-acid, prohormone form. In the in-

testine, the posttranslational processing of progluca-

gon and prosomatostatin differs, yielding as major

products glucagon-like peptide-1[7-36]-amide (GLP-

1[7-36]-amide) and the 28-amino-acid form of soma-

tostatin (SRIF-28), respectively.

Regulation of Secretion

0011 A wide range of nutrients, hormones, and neurotrans-

mitters are capable of influencing the secretion of

insulin, glucagon, somatostatin, and pancreatic poly-

peptide (Tables 1 and 2). In the case of insulin, the

major physiological regulator of b cell function is

the prevailing plasma glucose concentration. Other

metabolizable nutrients can mimic the stimulatory

action of glucose, but these other agents basically

act as modulators of the glucose response.

0012 Insulin acting locally within the islet is an influen-

tial inhibitor of glucagon secretion. Glucose inhib-

ition of glucagon secretion is thus attributable in

large part to concomitant stimulation of the b cell

with the release of insulin. g-Aminobutyric acid

(GABA), cosecreted with insulin from the b cell, has

also been suggested to contribute to inhibition of

cells. The paradoxical ability of amino acids and

food-activated elements of the enteroinsular axis to

stimulate glucagon as well as insulin secretion is often

considered to offer protection from hypoglycemia

that might result from the marked stimulation of

insulin release. An alternative interpretation is that

the stimulation of glucagon release serves to promote

insulin secretion by paracrine interaction within

the islet. Other situations associated with secretion

of glucagon include hypoglycemia, starvation, and

stress. In these circumstances, glucagon serves to

mobilize nutrient fuels from body stores to meet

immediate energy requirements.

Nutrient Regulation of Insulin Secretion

0013Although many factors influence the secretion of

pancreatic hormones, the regulation of insulin secre-

tion is particularly critical for normal metabolism

and maintenance of good health. b cell dysregulation

leading to deficient insulin secretion results in

impaired glucose tolerance, hyperglycemia and type

2 diabetes (also known as noninsulin-dependent dia-

betes mellitus). Hypersecretion of insulin may result

in life-threatening hypoglycemia, as observed in cer-

tain individuals with an islet cell tumor (insulinoma).

0014Nutrients exert direct and indirect effects on insulin

secretion. Thus, in addition to the direct stimulatory

actions of glucose, amino acids, and fatty acids on the

b cell, the ingestion of food and absorption of nutri-

ents trigger neural and hormonal elements of the

enteroinsular axis (Figure 2). Activation of the para-

sympathetic nerve innervating the islets liberates

acetylcholine from nerve terminals close to b cells.

Stimulation of intestinal endocrine cells leads to the

secretion of GLP-1[7–36]-amide, gastric-inhibitory

polypeptide (GIP) and cholecystokinin (CCK). These

agents are powerful insulin secretagogs at raised

glucose concentrations, and they markedly augment

the direct stimulatory actions of glucose and other

nutrients.

0015The mechanisms through which nutrients and

enteroinsular stimuli trigger insulin secretion from b

cells involve elevation of [Ca

2þ

]

and sensitization of

the exocytotic process to normal stimulatory action

of [Ca

2þ

]

(Figure 3). Metabolizable nutrients, includ-

ing glucose, certain amino acids, and fatty acids, act

by virtue of the ability of the b cell to metabolize these

substances with the generation of adenosine triphos-

phate (ATP). ATP generation results in closure of

ATP-sensitive potassium channels (K

ATP

) channels in

HORMONES/Pancreatic Hormones 3153

the plasma membrane, leading to membrane de-

polarization. This results in the opening of voltage-

dependent calcium channels (VDCCs) allowing Ca

2þ

to enter the b cell down its concentration gradient.

The subsequent increase of [Ca

2þ

]

triggers secretion

of insulin by exocytosis. Elevation of [Ca

2þ

]

helps to

restore the membrane potential through opening of

2þ

-sensitive K

channels in the plasma membrane.

Conditions of elevated [Ca

2þ

]

increase the sensitivity

of the b cell to the stimulatory actions of phospho-

lipase C and adenylate cyclase. Acetylcholine, CCK,

GLP-1[7-36]-amide and GIP are particularly potent

activators of these enzymes. Generation of IP

in-

hibits Ca

2þ

sequestration by the endoplasmic reticu-

lum, whereas protein kinase C (PKC) and cAMP

sensitize the secretory process to the stimulatory

action of Ca

2þ

. cAMP also activates protein kinase

(PK) responsible for phosphorylation of functionally

important proteins.

Physiological Actions

0016 Within the islet, insulin is the principal hormone that

appears to directly modulate the secretory activity of

other islet cell types. Outside the islet, insulin is the

anabolic hormone and driving force behind the regu-

lation of carbohydrate, protein and lipid metabolism

(Figure 4). Glucagon is the main catabolic counter-

regulatory hormone, but the net effect of glucagon is

more dependent on the insulin:glucagon molar ratio

rather than the absolute level of glucagon per se. The

minute-to-minute control of insulin and glucagon

secretion from the islets is therefore of paramount

importance in the overall regulation of nutrient

homeostasis.

0017Insulin and glucagon exert major effects on the

metabolism of carbohydrate, protein and lipid

(Table 3). The principal actions of insulin are to

lower circulating concentrations of glucose, amino

acids and fatty acids, to increase fat storage in adipose

tissue, and to promote the formation of muscle pro-

tein. Insulin achieves this by stimulating glucose and

amino acid uptake and by alteration of the activities

of enzymes in liver, muscle, and adipose tissue. These

enzymes mediate the effects of insulin on glycogen-

esis, glycogenolysis, gluconeogenesis, glycolysis, lipo-

genesis, lipolysis, ketogenesis, and both the synthesis

and degradation of protein. The actions of insulin on

these metabolic pathways are generally opposed by

the action of glucagon. Secretion of this counter-

regulatory hormone in conjunction with a decrease

in the insulin:glucagon molar ratio serves to generate

a catabolic response in times of need, involving mo-

bilization of nutrients from various tissue stores.

0018Somatostatin and PP secreted from the islets are

less significant in physiological terms than the other

two pancreatic hormones. Somatostatin and PP are

also found in endocrine cells of the intestine, and

they are both released into the circulation following

feeding.

Feeding

Digestion and

absorption of

nutrients

Gastrointestinal

peptide

secretions

Parasympathetic

nervous system

activation

β cell

(insulin)

Insulin exocytosis

(+)

(+) (+)

fig0002 Figure 2 Major neural and hormonal pathways regulating the insulin secretory response to feeding.

3154 HORMONES/Pancreatic Hormones

0019 Somatostatin is a potent inhibitor of secretion

from endocrine (pancreas, intestine, pituitary) and

exocrine cells, partly acting through paracrine

effects, thus contributing to the fine tuning of insulin

and glucagon secretion. Somatostatin also inhibits

the following aspects of gastrointestinal function,

largely as a result of inhibition of gut hormone

secretions: gastric acid secretion; secretion of

bile and pancreatic juice; gall bladder contraction;

intestinal motility; intestinal absorption; splanchnic

blood flow.

0020PP has been shown to exert various actions at

pharmacological concentrations. These include the

following: inhibiting exocrine and endocrine pancre-

atic secretions; gall bladder relaxation; increasing

gastrointestinal motility; inducing satiety. However,

there is presently little convincing evidence for a

physiological role of PP.

Feeding

Metabolism

Closure

Depolarization

Absorbed nutrients

(glucose, amino acids, fatty acids)

Secretory granule docking

Insulin exocytosis

GIP (+)

GLP-1 (+)

Epinephrine (−)

Norepinephrine (−)

Somatostatin (−)

Acetylcholine (+)

CCK (+)

DAG

PKC

[Ca

]

ATP

channel

influx

cAMP

PKA

ACPLC

fig0003 Figure 3 Direct and indirect actions of nutrients in the stimulation of insulin secretion from pancreatic b cells. AC, adenylate cyclase;

ATP, adenosine triphosphate; cAMP, cyclic AMP; [Ca

2þ

]

], cytoplasmic calcium ion concentration; CCK, cholecystokinin; DAG,

diacylglycerol; GIP, gastric inhibitory polypeptide; GLP-1[7-36]-amide, glucagon-like peptide-1[7-36]-amide; IP

, inositol 1,4,5-

triphosphate; K

ATP

channel, ATP-sensitive K

channel; PLC, phospholipase C; PKA, protein kinase A; PKC, protein kinase C.

tbl0003 Table 3 Major metabolic effects of insulin and glucagon on liver, muscle, and adipose tissue

Carbohydrate metabolism Proteinmetabolism Lipidmetabolism

Insulin glucagon Insulin glucagon Insulin glucagon

Blood glucose #"Blood amino acids # – Blood fatty acids #"

Glucose uptake (muscle,

adipose tissue)

" – Protein (muscle) "#Fat storage (adipose tissue) "#

Glycogenesis (liver,

muscle)

"#Amino acid uptake

(muscle, liver)

""Lipogenesis

(liver, adipose tissue)

Glycogenolysis (liver,

muscle)

#"Protein synthesis

(liver, muscle)

" – Lipolysis

(adipose tissue)

Gluconeogenesis (liver) #"Protein degradation

(liver, muscle)

#"Ketogenesis (liver) #"

Glycolysis (liver,

muscle, adipose tissue)

", stimulatory effect; #, inhibitory effect; –, no effect.

HORMONES/Pancreatic Hormones 3155

Mechanisms of Action

0021 Insulin and the other pancreatic hormones are se-

creted into the interstitial fluid; they cross the endo-

thelial barrier and enter the circulation. Effects at the

target cells are initiated by the action and binding

of the hormone to specific cell surface receptors

(Figure 5). The binding of the hormone to these recep-

tors initiates a sequence of postreceptor events ultim-

ately culminating in the various biological actions of

the hormone. Rapid events on the secretion of other

hormones are mediated by changes of [Ca

2þ

]

and the

activities of adenylate cyclase and phospholipase C

(see above). Stimulation of glucose uptake by muscle

and adipose tissue results from insulin-induced trans-

location of glucose transporter proteins (GLUT4)

from cytoplasmic vesicles to the plasma membrane.

Classical metabolic effects of insulin and glucagon at

target cells are achieved by activation and suppres-

sion of enzyme activity (so redirecting cell metabol-

ism) or by altering the rate of synthesis of enzymes at

the level of transcription and translation.

0022 Insulin binding to the external a-subunit of the

glycoprotein insulin receptor leads to a conforma-

tional change in the receptor that stimulates tyrosine

kinase activity. The activated the b-subunit auto-

phosphorylates at tyrosine sites in addition to phos-

phorylating intracellular proteins (Figure 5). Indeed it

is the tyrosine kinase activity that is essential for

insulin signaling. The best characterized postreceptor

signal transduction pathway centers around insulin-

receptor substrate 1 (IRS-1). Rapid tyrosine phos-

phorylation following insulin stimulation results in

noncovalent binding between phosphorylated sites

and specific domains on intracellular protein targets.

This ultimately results in the various important bio-

logical effects of insulin on target tissues (Figure 5).

Following initiation of postreceptor events, the insu-

lin–receptor complex is internalized by the target

cell, and whereas receptors are recycled to the cell

surface, insulin is degraded intracellularly. Elevated

insulin levels, for example in obesity or type 2 dia-

betes, results in insulin receptor ‘downregulation’

through decreasing numbers on the cell surface

and also by reducing tyrosine kinase activity of the

receptor.

Endocrine Pancreas in Diabetes

0023The two major forms of diabetes, type 1 insulin-

dependent diabetes mellitus and type 2 diabetes, are

associated with marked changes in the structure of

the endocrine pancreas. In long-standing type 1 dia-

betes, the insulin deficiency is the result of total auto-

immune destruction of b cells, while the mass of a

and PP cells remains virtually unchanged. How-

ever, in type 2 diabetes, the b cell mass is marginally

decreased in association with increases in the a

cell

Feeding

Absorbed nutrients

(glucose, amino acids, fatty acids)

Intestine

Muscle

Glycogenesis

Adipose tissue

Lipogenesis

β cell

(insulin)

Anabolic metabolic actions

of insulin

GLP-1[7-36]amide CCK GIP

fig0004 Figure 4 Insulin-mediated anabolic responses to feeding. CCK, cholecystokinin; GIP, gastric inhibitory polypeptide; GLP-1[7-36]-

amide, glucagon-like peptide-1[7-36]-amide.

3156 HORMONES/Pancreatic Hormones

mass and a

:b cell ratio. Hyperglucagonemia and

inappropriate a

cell function, both owing to a

lack of inhibition of glucagon secretion by insulin,

contribute to glucose intolerance and associated

metabolic disarray generally observed in diabetes.

0024 Type 2 diabetes is classically associated with de-

fective b cell function, normal or moderately raised

insulin concentrations, and insulin resistance. Insulin

secretory responses to glucose and other stimuli are

impaired in magnitude and kinetics. The b cells in

type 2 diabetics are also known to release excessive

amounts of proinsulin rather than insulin. Since

proinsulin cross-reacts with most antisera used to

measure insulin, actual concentrations of insulin in

type 2 diabetes are likely to be much lower than

previously estimated. Proinsulin and derived frag-

ments exhibit only 10–50% of the biological activity

of insulin, and therefore may contribute to the condi-

tion of insulin resistance.

See also: Diabetes Mellitus: Etiology; Chemical

Pathology; Treatment and Management; Problems in

Treatment; Secondary Complications