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E t I l A i

Updates in Diabetes & Endocrinology8-9.4.2015

Entero Insular Axis

Dr. Sherif Wagih MansourProfessor Of Physiology

Zagazig Faculty Of Medicine

• The term ‘Entero-insular Axis’ was coined by Unger &Eisentraut (1969) to include all those gut factorswhich contribute to enhanced insulin secretionfollowing ingestion of a meal.

• It is now apparent that the Entero-insular Axispossesses an important Neural, an Endocrine, andMetabolic component.

• Berthoud, (1984) estimated that Neurally-mediatedsecretion accounted for 20%, and Hormonal factors30%, of the insulin response to a liquid test meal.

Nauck M et al. J Clin Endocrinol Metab. 1986;63:492-498.

Entero-insular Axis

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• Cholinergic innervation is responsible for enhancingthe early insulin response to a meal, the so-called‘Cephalic phase’ of insulin release, which isindependent of absorption of nutrients. Cholinergicmechanisms are also involved in the enhancedinsulin secretion in obesity, the regulation of basaland post-prandial insulin secretion (Flatt & Bailey,

I. Neural component of Entero-Insular Axis

1984; Ahren et al. 1986).

• The pancreas is also innervated by Peptidergicneurones, many of which contain ‘gut peptides’ thatfunction as neurotransmitters. Vasoactive intestinalpeptide (VIP) and cholecystokinin (CCK)-containingneurones have been implicated in the regulation ofinsulin secretion.

II. Hormonal component of Entero-Insular Axis

• Many peptides isolated from intestinal and nervoustissue some, as Growth-hormone-releasing factor(GHRF), Vasoactive intestinal peptide (VIP) andGastrin-releasing peptide (GRP) share with Gastricinhibitory polypeptide (GIP) a considerable structuraly p yp p ( )similarity and an ability to stimulate insulinsecretion.

• The neuropeptide, Galanin, shares with Neurotensin(Which is found in endocrine cells of the smallintestine, where it leads to secretion and smoothmuscle contraction) and Somatostatin the ability tosuppress 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 gdevelopment.

• Amongst the nutrients, Carbohydrate is undoubtedly the major stimulant of insulin secretion. The so-called ‘Complex carbohydrates ’ are in general lesshyperglycaemic and stimulatory of insulin secretion than their constituent Mono-saccharides.

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• 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

d h l l i h l b t d t tand 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 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

GLP-1 and GIP Are Incretin Hormones

GLP-1 GIPIs 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 Best PractPract Res Res ClinClin EndocrinolEndocrinol MetabMetab. 2004;18:587. 2004;18:587––606. 606. 2.2. DruckerDrucker DJ. DJ. Diabetes CareDiabetes Care. 2003;26:2929. 2003;26:2929––2940.2940.

Glucagon secretion

Gastric emptying

CardioprotectionCardiac output

Appetite

Neuroprotection

GLP-1

Physiological Actions of GLPPhysiological Actions of GLP--1 and GIP1 and GIP

Glucose production

Glucose disposal

Insulin secretionInsulin biosynthesisΒ cell proliferationΒ cell apoptosis

LipogenesisOsteoblast

GIP

Sodium excretion

Drucker DJ. Cell Metab. 2006;3:153-165

Role of Role of IncretinsIncretins in Glucose in Glucose HomeostatisHomeostatis

B - cellsAlpha cellsB - cellsAlpha cells

Blood Blood GlucoseGlucoseBlood Blood GlucoseGlucose

Release of gut Release of gut hormones hormones ––

IncretinsIncretins

Ingestion of foodIngestion of food

Glucose Glucose uptake by uptake by musclesmuscles

Glucose Glucose uptake by uptake by musclesmuscles

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

ActiveActive

PancreasPancreas

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

InactiveInactiveGLPGLP--11

GI tractGI tract Glucose Glucose production production by liverby liver

Glucose Glucose production production by liverby liver

InactiveInactiveGIPGIP

DPPDPP--44enzymeenzyme

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

GLPGLP--1 & GIP1 & GIP

GLP-1 Has Many Beneficial Effects

• ↑ Insulin secretion to maintain glucose homeostasis• ↓ Glucagon secretion• ↓ Postprandial glycemia• ↓ Gastric emptying• ↑ Satiety due to delayed gastric emptying ↑ Sat ety due to de ayed gast c e pty g• ↓ 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.

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GLP-1 modes of action in humans• Stimulates glucose-dependent

insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

Upon ingestion of food…

EVIDENCE?

GLP-1 is secretedfrom the L-cellsin the intestine

This in turn…

Long term effectsdemonstrated in animals…

• Increases beta-cell mass andmaintains beta-cell efficiency

• Improves insulin sensitivity

• Reduces food intake

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

GLP-1 receptors are abundant

Nature Rev Endocrinology 8: 728

Pathophysiology of Type 2 Diabetes(Triad)

ImpairedIncretin Effect

ImpairedIncretin Effect

Relative InsulinRelative InsulinInsulinInsulinDeficiencyResistanceResistance

PrediabetesPrediabetes and and Type 2 DiabetesType 2 DiabetesPrediabetesPrediabetes and and Type 2 DiabetesType 2 Diabetes

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

Ominous Octet recentely -8-

IncreasedHGPHyperg lycemiaDEFN75-3/99 Decreased GUptak

Impa ired InsulinS ecretion Increased Li

DecreasedDecreasedIncretin EffectIncretin Effect

Decreased InsulinDecreased InsulinSecretionSecretion

Islet–Α cell

Increased Increased LipolysisLipolysis

IncreasedIncreasedHYPERGLYCEMIAHYPERGLYCEMIA

Reprinted with permission from DeFronzo R et al. Reprinted with permission from DeFronzo R et al. DiabetesDiabetes. 2009;58:773. 2009;58:773--795. 795. Copyright © 2009 American Diabetes Association. All rights reserved.Copyright © 2009 American Diabetes Association. All rights reserved.

IncreasedIncreasedHepatic GlucoseHepatic Glucose

ProductionProduction

IncreasedIncreasedGlucagonGlucagonSecretionSecretion

Decreased Glucose Decreased Glucose UptakeUptake

GlucoseGlucoseReabsorptionReabsorption

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

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Metabolism of Metabolism of GlucagonGlucagon--Like PeptideLike Peptide––11 and and GlucoseGlucose--Dependent Dependent InsulinotropicInsulinotropic PeptidePeptide

DPP-4

CapillaryCapillary

Active HormonesActive HormonesGLPGLP--1 [71 [7--36NH36NH22]]GIP [1GIP [1--42]42]

Inactive MetabolitesInactive MetabolitesGLPGLP--1 [91 [9--36NH36NH22]]GIP [3GIP [3--42]42]

• 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

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

AlphaAlpha--glucosidaseglucosidase inhibitorsinhibitors

IncretinsIncretinsInsulin secretionInsulin secretionGlucagon secretionGlucagon secretion

InhibitInhibitcarbohydratecarbohydratebreakdownbreakdown

IncretinsIncretinsSlow gastric emptyingSlow gastric emptying

SecretagoguesSecretagoguesSimulate insulin Simulate insulin

secretionsecretion

Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661–1669 |Drucker DJ. Mol Endocrinol. 2003;17:161–171.

ThiazolidinedionesThiazolidinedionesGlucose intakeGlucose intakeFFA outputFFA output

MetforminMetforminThiazolidinedionesThiazolidinediones

Glucose metabolismGlucose metabolism

MetforminMetforminThiazolidinedionesThiazolidinedionesSuppress 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-γ ↑ Peripheral insulin sensitivity

αα--GIsGIs acarbose, miglitol Blocks small bowelα-glucosidase

↓ Intestinal carbohydrate absorption

T2DM: Therapeutic Landscape (NonT2DM: Therapeutic Landscape (Non--insulin) 2012insulin) 2012

GLPGLP--1 R 1 R agonistsagonists

exenatide, liraglutide

Activates GLP-1 receptors

↑ Pancreatic insulin secretion;↓ glucagon secretion; delays gastric emptying; ↑ satiety

AmylinoAmylino--mimeticsmimetics

pramlintide Activates amylin receptors

↓ Pancreatic glucagon secretion; delays gastric emptying; ↑ satiety

DPPDPP--4 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

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D2 agonistsD2 agonists bromocriptine Activates dopaminergic receptors

‘Resets hypothalamic circadian organization’; ↑ insulin sensitivity

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.

Β-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 insulinPatients with renal failure, who decline insulin

• Elderly patients to avoid insulin & hypoglycemia

• Patients with increased incidence of hypoglycaemia (see e.g. ACCORD trial)

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Novel antidiabetic drugs

Dapagliflozin

SGLT-2 – Efficacy & Adverse effects

• HbA1c lowering by 0.5 - 0.8%• Dehydration• Increased creatinin & potassium• Uro genital infections• 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 Metformin2. The tablet should probably be Metformin

3. When this fails, use something else

References

1. Linda et al., Nutrition Research Reviews (1988), 1, 79-972. 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): S44. Diabetes Care 2015; 38(Suppl. 1): S4.

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