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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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