The document discusses the entero-insular axis, which refers to the gut factors that contribute to enhanced insulin secretion after eating a meal. It has neural, endocrine, and metabolic components. The neural component accounts for 20% of the insulin response via cholinergic innervation, while hormonal factors account for 30%. Key hormones involved are glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are secreted by the gut in response to food intake and potentiate insulin secretion. Impairment of the entero-insular axis is involved in the pathogenesis of type 2 diabetes due to reduced incretin effect. New diabetes therapies target this axis via dipeptidyl peptidase-4

1. Entero Insular Axis
Dr. Sherif Wagih Mansour
Professor Of Physiology
Zagazig Faculty Of Medicine
Updates in Diabetes & Endocrinology
8-9.4.2015

2. • The term ‘Entero-insular Axis’ was coined by Unger &
Eisentraut (1969) to include all those gut factors
which contribute to enhanced insulin secretion
following ingestion of a meal.
• It is now apparent that the Entero-insular Axis
possesses an important Neural, an Endocrine, and
Metabolic component.
• Berthoud, (1984) estimated that Neurally-mediated
secretion accounted for 20%, and Hormonal factors
30%, of the insulin response to a liquid test meal.
Nauck M et al. J Clin Endocrinol Metab. 1986;63:492-498.

3. Entero-insular Axis
1.
2.
3.

4. • Cholinergic innervation is responsible for enhancing
the early insulin response to a meal, the so-called
‘Cephalic phase’ of insulin release, which is
independent of absorption of nutrients. Cholinergic
mechanisms are also involved in the enhanced
insulin secretion in obesity, the regulation of basal
and post-prandial insulin secretion (Flatt & Bailey,
1984; Ahren et al. 1986).
• The pancreas is also innervated by Peptidergic
neurones, many of which contain ‘gut peptides’ that
function as neurotransmitters. Vasoactive intestinal
peptide (VIP) and cholecystokinin (CCK)-containing
neurones have been implicated in the regulation of
insulin secretion.
I. Neural component of Entero-Insular Axis

5. II. Hormonal component of Entero-Insular Axis
• Many peptides isolated from intestinal and nervous
tissue some, as Growth-hormone-releasing factor
(GHRF), Vasoactive intestinal peptide (VIP) and
Gastrin-releasing peptide (GRP) share with Gastric
inhibitory polypeptide (GIP) a considerable structural
similarity and an ability to stimulate insulin
secretion.
• The neuropeptide, Galanin, shares with Neurotensin
(Which is found in endocrine cells of the small
intestine, where it leads to secretion and smooth
muscle contraction) and Somatostatin the ability to
suppress insulin release under certain conditions.

6. III. Nutrients component of ENTERO-INSULAR AXIS
• The Entero-insular Axis in humans appears to begin
to function within the first few weeks of life and there
is evidence that dietary manipulation can affect
insulin secretion from the earliest stages of
development.
• Amongst the nutrients, Carbohydrate is undoubtedly
the major stimulant of insulin secretion. The so-called
‘Complex carbohydrates ’ are in general less
hyperglycaemic and stimulatory of insulin secretion
than their constituent Mono-saccharides.

7. • Several Amino acids stimulate insulin secretion by
direct action on the B-cells by increasing intracellular
Ca2+ in order to trigger exocytosis (Henquin, 1987).
Leucine, arginine and lysine are considered to be the
most potent stimulators, but alanine, glycine,
tryptophan, aspartate, isoleucine, asparagine, valine
and phenylalanine have also been reported to exert
stimulatory effects.
• Certain Free fatty acids and ketone bodies can exert
modest stimulatory effects on B-cell function in the
presence of glucose.

8. Incretins
• Gut-derived hormones, secreted in response to nutrient ingestion,
that potentiate insulin secretion from islet Β cells in a glucose-
dependent fashion, and lower glucagon secretion from islet Α cells
• Two predominant Incretins:
1. Glucagon-like peptide –1 (GLP-1) is synthesized in and secreted
from enteroendocrine L - cells found throughout the small and large
intestine, GLP-1 is also produced in the CNS, predominantly in the
brainstem, from where it is transported throughout the brain to elicit
metabolic, cardiovascular, and neuroprotective actions.
2. Glucose-dependent insulinotropic peptide (GIP) (also known as
gastric inhibitory peptide) is synthesized in and secreted from
enteroendocrine K cells located primarily in the duodenum and
proximal jejunum, and CNS production of GIP has also been
described.
• Incretin effect is impaired in type 2 diabetes

9. GLP-1 and GIP Are Incretin Hormones
GLP-1 GIP
 Is 30 amino acid peptide1
 Released from L - cells in ileum and
colon1,2
 Is 42 amino acid peptide2
 Released from K - cells in duodenum1,2
 Stimulates insulin response from
B -cells in a glucose-dependent
manner1
 Stimulates insulin response from
B- cells in a glucose-dependent
manner1
 Inhibits gastric emptying1,2  Has minimal effects on gastric
emptying2
 Reduces food intake and
body weight2
 Has insignificant effects on satiety and
body weight2
 Inhibits glucagon secretion from
A - cells in a glucose-dependent
manner1
 Does not appear to inhibit glucagon
secretion from A - cells1,2
1.1. Meier JJ et al.Meier JJ et al. Best Pract Res Clin Endocrinol MetabBest Pract Res Clin Endocrinol Metab. 2004;18:587–606.. 2004;18:587–606.
2.2. Drucker DJ.Drucker DJ. Diabetes CareDiabetes Care. 2003;26:2929–2940.. 2003;26:2929–2940.

10. Glucagon secretion
Glucose production
Glucose disposal
Insulin secretion
Insulin biosynthesis
Β cell proliferation
Β cell apoptosis
Gastric emptying
Cardioprotection
Cardiac output
Appetite
Neuroprotection
Lipogenesis
Osteoblast
GLP-1
GIP
Physiological Actions of GLP-1 and GIPPhysiological Actions of GLP-1 and GIP
Sodium excretion
Drucker DJ. Cell Metab. 2006;3:153-165

11. Role of Incretins in Glucose HomeostatisRole of Incretins in Glucose Homeostatis
DPP-4=dipeptidyl peptidase–4
GIP=glucose-dependent insulinotropic peptide
GLP-1=glucagon-like peptide–1
B - cells
Alpha cells
InactiveInactive
GLP-1GLP-1
BloodBlood
GlucoseGlucose
BloodBlood
GlucoseGlucose
GI tractGI tract
Release of gutRelease of gut
hormones –hormones –
IncretinsIncretins
Ingestion of foodIngestion of food
GlucoseGlucose
uptake byuptake by
musclesmuscles
GlucoseGlucose
uptake byuptake by
musclesmuscles
GlucoseGlucose
productionproduction
by liverby liver
GlucoseGlucose
productionproduction
by liverby liver
InactiveInactive
GIPGIP
DPP-4DPP-4
enzymeenzyme
GlucoseGlucose
dependentdependent
glucagon fromglucagon from
alpha cellsalpha cells
(GLP-1)(GLP-1)
Glucose-Glucose-
dependentdependent
insulin from betainsulin from beta
cellscells
(GLP-1, GIP)(GLP-1, GIP)
ActiveActive
GLP-1 & GIPGLP-1 & GIP
PancreasPancreas

12. GLP-1 Has Many Beneficial Effects
• ↑ Insulin secretion to maintain glucose homeostasis
• ↓ Glucagon secretion
• ↓ Postprandial glycemia
• ↓ Gastric emptying
• ↑ Satiety due to delayed gastric emptying
• ↓ Food ingestion due to effects on brain
• ↑ Β cell number and ↑ Β cell mass (animal studies)
– ↑ Β cell proliferation and ↑ islet neogenesis
– ↓ Apoptosis
Ranganath LR et al. J Clin Pathol. 2008;61:401-409.

13. GLP-1 modes of action in humans
GLP-1 is secreted
from the L-cells
in the intestine
This in turn…
• Stimulates glucose-dependent
insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
Long term effects
demonstrated in animals…
• Increases beta-cell mass and
maintains beta-cell efficiency
• Improves insulin sensitivity
• Reduces food intake
Upon ingestion of food…
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412
Drucker DJ. Mol Endocrinol 2003; 17:161-171
EVIDENCE?

14. Nature Rev Endocrinology 8: 728
GLP-1 receptors are abundant

16. Pathophysiology of Type 2 Diabetes
(Triad)
Impaired
Incretin Effect
Impaired
Incretin Effect
Relative Insulin
Deficiency
Relative Insulin
Deficiency
Insulin
Resistance
Insulin
Resistance
Prediabetes andPrediabetes and
Type 2 DiabetesType 2 Diabetes
Prediabetes andPrediabetes and
Type 2 DiabetesType 2 Diabetes
Kendall DM, Cuddihy, RM, Bergenstal RM. Provided by David M. Kendall. MD.

17. Reprinted with permission from DeFronzo R et al.Reprinted with permission from DeFronzo R et al. DiabetesDiabetes. 2009;58:773-795.. 2009;58:773-795.
Copyright © 2009 American Diabetes Association. All rights reserved.Copyright © 2009 American Diabetes Association. All rights reserved.
Ominous Octet recentely -8-
Increa sed
HG PHyp
erglyce mia
ETIOL OGYOF T2DM
DEFN75-3/99
Decrea sedGluco se
U ptake
Impaired Insulin
Secre tion
Increase dLipolys is
DecreasedDecreased
Incretin EffectIncretin Effect
Decreased InsulinDecreased Insulin
SecretionSecretion
IncreasedIncreased
Hepatic GlucoseHepatic Glucose
ProductionProduction
Islet–Α cell
IncreasedIncreased
GlucagonGlucagon
SecretionSecretion
Decreased GlucoseDecreased Glucose
UptakeUptake
IncreasedIncreased
LipolysisLipolysis
IncreasedIncreased
GlucoseGlucose
ReabsorptionReabsorption
HYPERGLYCEMIAHYPERGLYCEMIA
NeurotransmitterNeurotransmitter
DysfunctionDysfunction

18. Incretin-Based Therapies
• Dipeptidyl peptidase–4 Inhibitors (incretin enhancers)
– Sitagliptin – Saxagliptin - Linagliptin (no dose
adjustment in renal insufficiency) – Vildagliptin –
Alogliptin.
• Glucagon-like peptide–1 Agonists (incretin Mimetics)
– Exenatide , bid – Liraglutide, once daily - Exenatide
LAR, once weekly
– Albiglutide - Taspoglutide

20. Metabolism ofMetabolism of Glucagon-Like Peptide–1Glucagon-Like Peptide–1 andand
Glucose-Dependent Insulinotropic PeptideGlucose-Dependent Insulinotropic Peptide
DPP-4
CapillaryCapillary
• Dipeptidyl peptidase–4 (DPP-4)
– Ubiquitous, specific protease
– Cleaves N-terminal dipeptide
– Inactivates >50% of GLP-1 ~1 min
>50% of GIP in ~7 min
Active HormonesActive Hormones
GLP-1 [7-36NHGLP-1 [7-36NH22]]
GIP [1-42]GIP [1-42]
Inactive MetabolitesInactive Metabolites
GLP-1 [9-36NHGLP-1 [9-36NH22]]
GIP [3-42]GIP [3-42]
GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1

21. Therapy for Type 2 Diabetes:Therapy for Type 2 Diabetes:
Sites of ActionSites of Action
Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661–1669 |
Drucker DJ. Mol Endocrinol. 2003;17:161–171.
Alpha-glucosidase inhibitorsAlpha-glucosidase inhibitors
IncretinsIncretins
 Insulin secretionInsulin secretion
 Glucagon secretionGlucagon secretion
InhibitInhibit
carbohydratecarbohydrate
breakdownbreakdown
IncretinsIncretins
Slow gastric emptyingSlow gastric emptying
SecretagoguesSecretagogues
Simulate insulinSimulate insulin
secretionsecretion
ThiazolidinedionesThiazolidinediones
 Glucose intakeGlucose intake
 FFA outputFFA output
MetforminMetformin
ThiazolidinedionesThiazolidinediones
 Glucose metabolismGlucose metabolism
MetforminMetformin
ThiazolidinedionesThiazolidinediones
Suppress glucose productionSuppress glucose production

22. Agent Examples Mechanism Action
SUsSUs glyburide, glipizide,
glimepiride
Closes KATP channels ↑ Pancreatic insulin secretion
‘‘GlinidesGlinides repaglinide,
nateglinide
Closes KATP channels ↑ Pancreatic insulin secretion
BiguanidesBiguanides metformin Activates AMP-kinase ↓ Hepatic glucose production
TZDsTZDs rosiglitazone,
pioglitazone
Activates PPAR-γ ↑ Peripheral insulin sensitivity
αα-GIs-GIs acarbose, miglitol Blocks small bowel
α-glucosidase
↓ Intestinal carbohydrate
absorption
GLP-1 RGLP-1 R
agonistsagonists
exenatide,
liraglutide
Activates GLP-1
receptors
↑ Pancreatic insulin secretion;
↓ glucagon secretion; delays
gastric emptying; ↑ satiety
Amylino-Amylino-
mimeticsmimetics
pramlintide Activates amylin
receptors
↓ Pancreatic glucagon secretion;
delays gastric emptying; ↑ satiety
DPP-4DPP-4
inhibitorsinhibitors
sitagliptin,
saxagliptin
Inhibits DPP-4,
↑ endogenous incretins
↑ Pancreatic insulin secretion;
↓ pancreatic glucagon secretion
Bile acidBile acid
sequestrantssequestrants
colesevelam Binds bile acid
cholesterol
?
D2 agonistsD2 agonists bromocriptine Activates dopaminergic
receptors
‘Resets hypothalamic circadian
organization’; ↑ insulin sensitivity
T2DM: Therapeutic Landscape (Non-insulin) 2012T2DM: Therapeutic Landscape (Non-insulin) 2012
Inzucchi SE et al. Diabetes Care 2012;35:1364-1379.

23. Comparison of Incretin ModulatorsComparison of Incretin Modulators
GLP-1 Analogues DPP-4 Inhibitors
Administration route Injection Oral
 GLP-1 Sustained Meal-related
Effect on A1C  
Effects on body weight   
Side effects
Nausea,
Rare: pancreatitis
(Well tolerated)
Nasopharyngitis, skin rashes,
Stevens-Johnson syndrome: a
form of toxic epidermal necrolysis, is a
life-threatening skin condition, in
which cell death causes
the epidermis to separate from
the dermis.
Β-cell function  
GLP-1=glucagon-like peptide–1; DDP-4=dipeptidyl peptidase–4

24. When to use DPP-4 inhibitors
(in 2013)
• 3rd
oral agent after metformin and sulfonylureas,
when the patient refuses insulin
• Patients with renal failure, who decline insulin
• Elderly patients to avoid insulin & hypoglycemia
• Patients with increased incidence of
hypoglycaemia (see e.g. ACCORD trial)

25. Novel antidiabetic drugs
Dapagliflozin

26. SGLT-2 – Efficacy & Adverse effects
• HbA1c lowering by 0.5 - 0.8%
• Dehydration
• Increased creatinin & potassium
• Uro-genital infections
BMC Medicine 11: 43f

27. Current ADA / EASD 2015 guidelines for T2DM

28. Evidence-based Pharmacotherapy of T2DM
in 2014
1. When diet fails, use a tablet
2. The tablet should probably be Metformin
3. When this fails, use something else

29. References
1. Linda et al., Nutrition Research Reviews (1988), 1, 79-97
2. Higgins et al., 2008: Clinical Chemistry and Laboratory Medicine; 46(1):43-56.
3. Campbell et al., (2013): Pharmacology, Physiology, and Mechanisms of Incretin
Hormone Action .Cell Metabolism 17:1-19, June 4, 2013 .
4. Diabetes Care 2015; 38(Suppl. 1): S4.

30. Thank you 