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THE ENDOCRINE SYSTEM,

METABOLISM AND DISORDERS

INSULIN SECRETION & INSULIN


ACTION
Dr. dr. Made Ratna Saraswati, SpPD-KEMD,
FINASIM

Endocrinology and Metabolism Division, Department of


Internal Medicine
Faculty of Medicine, Udayana University/Sanglah
Hospital, Denpasar

26th October 30th November 2015


References
Gardner DG, Shoback D (editors).
Greenspan's Basic & Clinical Endocrinology.
9th edition. New York: McGrawHill, 2011.
Harrisons Principles of Internal Medicine 17th ed.
McGraw Hill 2008. (Part 15 Endocrinology and
Metabolism)

Perkeni, 2015. Petunjuk praktis pengelolaan


diabetes melitus tipe 2. Perkumpulan Endokrinologi
Indonesia. Jakarta.
American Diabetes Association (ADA) Clinical
Practice Recommendations. Diabetes Care 2015.
The Pancreas
The pancreas comprises two
functionally distinct organs:
The exocrine pancreas
the major digestive gland of the
body; and
The endocrine pancreas
The Endocrine Pancreas
F ig. Human islet of
Langerhans.
insulin (red)
glucagon (green)
somatostatin (blue)

Staining was performed by


immunofluorescence and
imaged by confocal
microscopy.
(Reproduced, with permission,
from Cabrera 0, Berman DM,
Kenyon NS, Ricordi C,
Berggren PO, Caicedo A. The
unique cytoarchitecture of
Masharani U, German MS. Pancreatic hormoneshuman and Diabetespancreatic islets
Mellitus. In: Gardner DG, has
Shoback
implications
D (editors). Greenspan's Basic & Clinical Endocrinology. forYork:
9 edition. New
th
islet cell 2011.
McGrawHill,
Table 1. Cell types in adult human pancreatic islets of
Langerhans

Cell Types Approximat Secretory Products


e
percentage
of Islet
Volume
cell 25% Glucagon
Proglucagon
cell 55% Insulin
C peptide
Proinsulin
Islet amylod polypeptide
(lAPP)
y-aminobutyric acid
Masharani U, German MS. Pancreatic hormones and Diabetes Mellitus. In: Gardner DG, Shoback
(GABA)
D (editors). Greenspan's Basic & Clinical Endocrinology. 9 edition. New York: McGrawHill, 2011.
th
Pancreatic beta cell

F ig. Structural components of the pancreatic cell


involved in glucose-induced biosynthesis and release of
insulin.
(Modified and reproduced, with permission, from Junqueira LC,
Carneiro
Masharani J, LongMS.
U, German JA.Pancreatic
Basic Histology.
hormones and5th ed.Mellitus.
Diabetes McGraw-Hill;
In: Gardner1986.)
DG, Shoback
D (editors). Greenspan's Basic & Clinical Endocrinology. 9 th edition. New York: McGrawHill, 2011.
Insulin

Fig. Structure of human proinsulin C peptides and


insulin molecules connected at two sites by dipeptide
links.
Masharani U, German MS. Pancreatic hormones and Diabetes Mellitus. In: Gardner DG, Shoback
D (editors). Greenspan's Basic & Clinical Endocrinology. 9 th edition. New York: McGrawHill, 2011.
Insulin Secretion

First phase Second phase

Basal
concentrati
on

F ig. Multiphasic response of the in vitro


perfused rat pancreas during constant
stimulation with glucose.
(Modified from Grodsky GM, et al. Further studies o n the dynamic aspects of
insulin release
Masharani in vitro
U, German with evidence
MS. Pancreatic for aand
hormones two-compartmental
Diabetes Mellitus. In:storage
Gardnersystem.
DG, Shoback
Acta
D (editors). Greenspan's Diabetol
Basic Lat.
& Clinical 1 969;6 [suppl
Endocrinology. 1 ] :554.)
9 edition.
th
New York: McGrawHill, 2011.
Fig. A simplified outline of glucose-sensing
and regulated insulin secretion from the cell.
Masharani U, German MS. Pancreatic hormones and Diabetes Mellitus. In: Gardner DG, Shoback
D (editors). Greenspan's Basic & Clinical Endocrinology. 9 th edition. New York: McGrawHill, 2011.
Table. Regulation of insulin release
Stimulants of Glucose
insulin Amino acids: Leucine
release Neural: Vagal stimulation, acetylcholine
Drugs: Sulfonylureas, meglitinides
Amplifiers of Enteric hormones:
glucose induced Glucagon-like peptide 1 (7-37) (GLP1 )
insulin Gastric inhibitory peptide (GIP)
release Cholecystokinin, Gastrin, Secretin
Neural: -adrenergic effect of
catecholamines
Amino acids: arginine
Drugs: GLPl agonists
Inhibitors of Neural: a-adrenergic effect of
insulin catecholamines
Masharani U, German MS. Pancreatic hormones and Diabetes Mellitus. In: Gardner DG, Shoback
Drelease Humoral:
(editors). Greenspan's Basic somatostatin
& Clinical Endocrinology. 9 th edition. New York: McGrawHill, 2011.
F ig. A simplified outline of insulin signaling .

Masharani U, German MS. Pancreatic hormones and Diabetes Mellitus. In: Gardner DG, Shoback
D (editors). Greenspan's Basic & Clinical Endocrinology. 9 th edition. New York: McGrawHill, 2011.
Metabolic Effect of Insulin
Paracrine effect
The effects of the products of
endocrine cells on surrounding cells
Endocrine effect
Table. Endocrine effect of insulin

Tissue Effect of Insulin


Liver Catabolic Pathways
Inh ibits glycogenolysis
Inh ibits conversion of fatty acids and amino acids to keto acids
Inhibits conversion of amino acids to gl ucose
Anabolic Pathways
Promotes glucose storage as glycogen (induces glucokinase and glycogen
synthase, inhibits phosphorylase)
Increases triglyceride synthesis and VLDL formation
Muscle Protein Synthesis
I ncreases amino acid transport, Increases ribosomal protein synthesis
Glycogen Synthesis
Increases g l ucose transport, Induces glycogen synthethase
Inhibits phosphorylase
Adipose Triglyceride Storage
Tissue Lipoprotein lipase is ind uced by insulin to hydrolyze triglycerides in circulating
li poproteins for delivery of fatty acids to the adipocytes
Glucose transport into cell provides glycerol phosphate to permit esterification
of fatty
acids suppl ied by l ipoprotein transport
Masharani U, German MS. Pancreatic
Intracellular lipase is hormones
inhibited byand Diabetes Mellitus. In: Gardner DG, Shoback
insulin
D (editors). Greenspan's Basic & Clinical Endocrinology. 9 th edition. New York: McGrawHill, 2011.
Glucose Transporter Protein
Glucose oxidation provides energy for most cells
and i s critical for brain ftmction.
Because cell membranes are impermeable to
hydrophilic molecules such as glucose, all cells
require carrier proteins to transport glucose across
me lipid bilayers into the cytosol.
All other cells utilize non-energy-dependent
transporters that facilitate diffusion of glucose
from a higher concentration to a lower
concentration across cell membranes.
Facilitative glucose transporters (GLUTs) comprise
a large family including at least 13 members,
although some of the recently identified members
of the family have not yet been shown to transport
glucose.
GLUT 1
present in all human tissues. It mediates basal glucose uptake,
because it has a very high affinity for glucose and, therefore, can
transport glucose at the relatively low concentrations found in the
fasted state. For this reason, its presence on the surface of the
endothelial cells of the brain vascular system (blood-brain barrier)
ensures adequate transport of plasma glucose into the central
nervous system.
GLUT 2
has a lower affinity for glucose and Thus increases glucose
transport when plasma glucose levels rise, such as postprandially.
It is a major transporter of glucose in hepatic, intestinal, and renal
tubular cells.
The low affinity of GLUT 2 for glucose reduces hepatic uptake of
glucose during fasting, while its ability to transport glucose equally
efficiently in both directions assists in the export of glucose from
hepatocytes.
GLUT 3
also found in all tissues, the major glucose transporter on neurons.
It also has a very high affinity for glucose and is responsible for
transferring glucose into neuronal cells at the lower concentrations
found in the central nervous system.
GLUT 4
found in two major insulin target tissues: skeletal muscle and
adipose tissue. It is sequestered mainly within an intracellular
Learning Task
Explain the cells types and hormone
secreted by islets of Langerhans!
Describe how insulin secretion is
regulated!
Describe the metabolic action of
insulin!
Describe how glucagon release is
regulated and summarize its main
action!
THANK YOU

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