Entero Insular Axis

Dr. Sherif Wagih MansourProfessor Of Physiology

Zagazig Faculty Of Medicine

Updates in Diabetes & Endocrinology8-9.4.2015

• 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.

Entero-insular Axis

1.

2.

3.

• 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

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.

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.

• 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.

Incretins

• Gut-derived hormones, secreted in response to nutrient ingestion, that potentiate insulin secretion from islet cells in a glucose-dependent fashion, and lower glucagon secretion from islet 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

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.

Glucagon secretion

Glucose production

Glucose disposal

Insulin secretionInsulin biosynthesis cell proliferation cell apoptosis

Gastric emptying

CardioprotectionCardiac output

Appetite

Neuroprotection

LipogenesisOsteoblast

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

Role of Incretins in Glucose HomeostatisRole of Incretins in Glucose Homeostatis

DPP-4=dipeptidyl peptidase–4GIP=glucose-dependent insulinotropic peptideGLP-1=glucagon-like peptide–1

B - cellsAlpha cellsB - cellsAlpha cells

InactiveInactiveGLP-1GLP-1

Blood Blood Glucose Glucose

Blood Blood Glucose Glucose

GI tractGI tract

Release of gut Release of gut hormones –hormones –

IncretinsIncretins

Ingestion of foodIngestion of food

Glucose Glucose uptake by uptake by

muscles muscles

Glucose Glucose uptake by uptake by

muscles muscles

Glucose Glucose production production

by liver by liver

Glucose Glucose production production

by liver by liver

InactiveInactiveGIPGIP

DPP-4DPP-4enzymeenzyme

Glucose Glucose dependent dependent glucagon from glucagon from alpha cells alpha cells (GLP-1)(GLP-1)

Glucose-Glucose-dependent dependent insulin from beta insulin from beta cells cells (GLP-1, GIP)(GLP-1, GIP)

ActiveActiveGLP-1 & GIPGLP-1 & GIP

PancreasPancreas

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.

GLP-1 modes of action in humans

GLP-1 is secretedfrom the L-cellsin the intestine

This in turn…

• Stimulates glucose-dependent insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

Long term effectsdemonstrated 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; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

EVIDENCE?

Nature Rev Endocrinology 8: 728

GLP-1 receptors are abundant

Pathophysiology of Type 2 Diabetes(Triad)

ImpairedIncretin Effect

ImpairedIncretin Effect

Relative InsulinDeficiency

Relative InsulinDeficiency

InsulinResistance

InsulinResistance

Prediabetes and Prediabetes and Type 2 DiabetesType 2 Diabetes

Prediabetes and Prediabetes and Type 2 DiabetesType 2 Diabetes

Kendall DM, Cuddihy, RM, Bergenstal RM. Provided by David M. Kendall. MD.

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-

In c re a s e dH G P

H y p e rg ly c e m ia

E T IO L O G Y O F T 2 D M

D E F N 7 5 -3 /9 9 D e c re a s e d G lu c o s eU p ta k e

Im p a ire d In s u linS e c re tio n In c re a s e d L ip o ly s is

DecreasedDecreasedIncretin EffectIncretin Effect

Decreased InsulinDecreased InsulinSecretionSecretion

IncreasedIncreasedHepatic GlucoseHepatic Glucose

ProductionProduction

Islet– cell

IncreasedIncreasedGlucagonGlucagonSecretionSecretion

Decreased Glucose Decreased Glucose UptakeUptake

Increased Increased LipolysisLipolysis

IncreasedIncreasedGlucoseGlucose

ReabsorptionReabsorption

HYPERGLYCEMIAHYPERGLYCEMIA

NeurotransmitterNeurotransmitterDysfunctionDysfunction

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

Metabolism of Metabolism of Glucagon-Like Peptide–1Glucagon-Like Peptide–1 and and 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

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

InhibitInhibitcarbohydratecarbohydratebreakdownbreakdown

IncretinsIncretins

Slow gastric emptyingSlow gastric emptying

SecretagoguesSecretagoguesSimulate insulin Simulate insulin

secretionsecretion

ThiazolidinedionesThiazolidinediones Glucose intakeGlucose intake

FFA outputFFA output

MetforminMetforminThiazolidinedionesThiazolidinediones Glucose metabolismGlucose metabolism

MetforminMetforminThiazolidinedionesThiazolidinediones

Suppress glucose productionSuppress glucose production

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- Peripheral insulin sensitivity

-GIs-GIs acarbose, miglitol Blocks small bowel-glucosidase

Intestinal carbohydrate absorption

GLP-1 R GLP-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-4 DPP-4 inhibitorsinhibitors

sitagliptin, saxagliptin

Inhibits DPP-4, endogenous incretins

Pancreatic insulin secretion; pancreatic glucagon secretion

Bile acid Bile 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.

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 effectsNausea,

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.

-cell function

GLP-1=glucagon-like peptide–1; DDP-4=dipeptidyl peptidase–4

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)

Novel antidiabetic drugs

Dapagliflozin

SGLT-2 – Efficacy & Adverse effects

• HbA1c lowering by 0.5 - 0.8%

• Dehydration

• Increased creatinin & potassium

• Uro-genital infections

BMC Medicine 11: 43f

Current ADA / EASD 2015 guidelines for T2DM

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

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.

Thank you