References

ENDOCRINE PANCREAS
PHYSIOLOGY
EM Savoeun, MD
ICU Medical (KSFH)
 Introduction
Four polypeptides secreted by the islets of Langerhans in
the pancreas
– hormones insulin
– hormones glucagon
– polypeptide, somatostatin, plays a role in the regulation of
islet cell secretion
– pancreatic polypeptide, is probably concerned primarily
with the regulation of HCO–3 secretion to the intestine

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 Introduction
• Insulin is anabolic, increasing the storage of glucose,
fatty acids, and amino acids.
– Insulin excess causes hypoglycemia, which leads to
convulsions and coma.
– Insulin deficiency, either absolute or relative, causes
diabetes mellitus
• Glucagon is catabolic, mobilizing glucose, fatty acids,
and the amino acids from stores into the bloodstream.
– Glucagon deficiency can cause hypoglycemia
– Glucagon excess makes diabetes worse.
– Excess pancreatic production of somatostatin causes
hyperglycemia and other manifestations of diabetes.

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 termes
• glycogenolysis: “glycogen breakdown”
increase the use of fats and excess amino
acids for energy production
• gluconeogenesis: “making new glucose”
• glycogenesis: “glycogen production”

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 Islet Cell Structure
• Humans have at least four distinct cell types:
A, B, D, and F cells. A, B, and D cells are also
called ,  and  cells
– A cells secrete glucagon (20%)
– B cells secrete insulin (60–75%) -islets make up
about 2% of the volume of the gland
– D cells secrete somatostatin
– F cells secrete pancreatic polypeptide

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 Structure

Preprohormone:
– Hormone insulin : 51 amino-
acide
• Deux chaînes « α » et « β »
• Deux ponts disulfures
– Peptide C

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 Glucose
Blood
Glut 2

Glucose Close of channel K+ Open of channel Ca++

Hexokinase

G6P

Depolarisation of membrane
-Cells
 ATP

Insulin Blood
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 Properties of insulin and glucagon
Water soluble
– Carried dissolved in plasma – no special transport
proteins
– Interact with cell surface receptors on target cells

Insulin and Glucagon

Insulin Glucagon
• Target tissues: liver, • Target tissue is liver
adipose tissue, muscle,
and satiety center of • Causes breakdown of
hypothalamus glycogen and fats for
• Increases uptake of energy
glucose and amino acids
by cells
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Negative feedback regulation of
the secretion of glucagon (blue
arrows) and insulin (orange
arrows)

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Regulation of Glucagon and Insulin
Secretion
Factor Insulin Glucagon
Nutrients:
- glucose  5mM + -
- glucose  5mM - +
-  amino acids + +
-  fatty acids + 0
Hormones/neurotransmitters:
- GI tract (GPI...) + 0
- Adrenaline - +
- noradrenaline - +
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Effects of islet cell hormones on the secretion
of other islet cell hormones

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 Insulin and Insulinlike Activity in Blood

Insulin-like growth factor 1 (IGF-1) 14

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Effects of Insulin

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Actions of insulin on adipose tissue; skeletal, cardiac, and
smooth muscle and the liver

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Glucose Transporters

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Why keep blood glucose concentration
constant?
• Some tissues only metabolise glucose: CNS,
Red blood cells, kidney, eye
• Metabolise glucose at constant rate
• Rate of glucose uptake determined by blood
glucose concentration
 Keep blood glucose concentration to enable
metabolism to proceed at constant rate.

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 Processes affected by insulin and
glucagon
Process Insulin Glucagon
Glucose uptake : muscle and + 0
adipose tissue
Gluconeogenesis: liver - +
Glycogenesis: liver and + -
muscle
Glycogenolysis: liver - +

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 Processes affected by insulin and
glucagon
Process Insulin Glucagon
Lipogenesis: liver and adipose + -
tissue
Lipolysis: adipose tissue - +/-
Ketogenesis: liver - +
Amino acid uptake: muscle + 0
Protein synthesis + 0

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 Additional metabolic problems due to
insulin deficiency
Muscle:
 uptake of amino acids and protein synthesis ( proteolysis)

Adipose tissue:
 esterification ( lipolysis)

Liver:
 gluconeogenesis from muscle amino acids
 ketogenesis from adipose tissue fatty acids
Consequences:
– muscle wasting and weight loss
– hyperglycaemia Disordered plasma glucose
– ketosis homeostasis in insulin deficiency.
The heavy arrows indicate reactions that are
accentuated. The rectangles across arrows indicate
reactions that are blocked.
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Integrated control of blood glucose
concentration

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 What happens to metabolism when insulin or
glucagon levels are abnormal?
• Insulin
– High  hypoglycaemia
– Low  diabetes

• Glucagon
– High  no significant effect
– Low  no significant effect

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 Hypoglycaemia
• Blood glucose < 3.0 mM
• Uptake of glucose by glucose-
dependent tissues not adequate to
maintain tissue function.
• CNS very sensitive:
– Impaired vision, slurred speech,
staggered walk
– Mood change – aggressive
– Confusion, coma, death
• Stress response (release of
adrenaline):
– Pale
– Sweating - clammy Plasma glucose levels at which various
effects of hypoglycemia appear

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 Diabetes Mellitus
 Group of metabolic diseases
 Affect 3-4% of population in Cambodia
 Characterised by:
– chronic hyperglycaemia (prolonged elevation of blood
glucose)
– leading to long-term clinical complications
Caused by:
– Insulin deficiency – failure to secret adequate amounts of
insulin from -cells
and/ or
– Insulin resistance – tissues become insensitive to insulin

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 Classification of Diabetes
Two major types recognised clinically
– Type 1 – absolute insulin deficiency (loss of -
cells)
– Type 2 – relative insulin deficiency and/or insulin
resistance
Also Gestational Diabetes (only occurs during
pregnancy)

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 Causes of hyperglycaemia
Insulin deficiency and/or insulin resistance affects:
Muscle:
–  uptake of glucose
–  glycogenesis
Adipose tissue:
–  uptake of glucose
–  lipogenesis and esterification
Liver
–  glycogenesis and glycolysis
–  gluconeogenesis
Oral glucose tolerance test
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Glucose tolerance testing

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 Clinical consequences of
hyperglycaemia
Acute – metabolic:
– glycosuria (exceeds renal threshold)
– polyuria (excess urine production)
– polydipsia (thirst)
Chronic – microvascular disease:
– eye disease including retinopathy
– kidney (nephropathy)
– peripheral nervous system (neuropathy)
Chronic – macrovascular disease:
– coronary artery disease
– stroke
– poor peripheral circulation (feet)

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Effects of insulin deficiency

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Factors that stimulate and inhibit
insulin secretion

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Factors that stimulate and inhibit
glucagon secretion

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 ADA Clinical Practice Recommendations
Diagnosis of Diabetes
• A1C  6.5%
– Test performed NGSP certified and standardized to DCCT*
• FPG  126 mg/dl
– No caloric intake for at least 8 hours*
• 2 hour glucose  200 mg/dl during an OGTT
– Test performed as per WHO (75 g glucose)*
• If classic symptoms of hyperglycemia = random glucose  200 mg/dl

NORMAL PREDIABETES IFG or IGT DIABETES

FPG < 100 FPG > 100 – 125 (IFG) FPG > 126

2-h PG < 140 2-h PG 140 – 199 (IGT) 2-h PG > 200

A1c < 5.7% A1c 5.7 – 6.4% A1c > 6.5%

NGSP : National Glycohemoglobin Standardization Program
*In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing
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American Diabetes Association. Diabetes Care 323(Suppl 1), 2009
 Screening for and diagnosis of
GDM

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DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013
 Pathogenesis of type 2 Diabetes
Diabetes
Normal glucose tolerance
insulin Secretion

1st phase 2 nd phase

-10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

I.V. Glucose Duration (minutes)

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Adapté de Weyer, et al. J Clin Invest. 1999; Ward, et al. Diabetes Care. 1984.
 Natural History of Type 2 Diabetes
350
(mg/dL)

Post-meal glucose
300
250
Glucose

200 Fasting glucose

150
100
50
Relative Function

250
200 Insulin resistance
( cell)

150
100
Insulin level
50
Incretin action
0
-15 -10 -5 0 5 10 15 20 25 30
Pre-diabetes Onset Years
metabolic syndrome Diabetes

Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 ; DeFronzo RA. Diabetes. 37:667, 1988; Saltiel J. Diabetes. 45:1661-1669, 1996.
Robertson RP. Diabetes. 43:1085, 1994; Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777.
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