pancreas endocrine.pdf
TRANSCRIPT
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EM Savoeun, MD ICU Medical (KSFH)
Endocrine PANCREAS Physiology
References
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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 HCO3 secretion to the intestine
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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.
Introduction
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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 (6075%) -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 chanes et Deux ponts disulfures
Peptide C
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Glucose
Glucose
Glut 2
G6P
ATP
Hexokinase
Depolarisation of membrane
Close of channel K+ Open of channel Ca++
Insulin
Blood
Blood
-Cells
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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
Target tissues: liver, adipose tissue, muscle, and satiety center of hypothalamus
Increases uptake of glucose and amino acids by cells
Glucagon
Target tissue is liver
Causes breakdown of glycogen and fats for energy
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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...) - Adrenaline - noradrenaline
+ - -
0 + +
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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
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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 adipose tissue
+ 0
Gluconeogenesis: liver - +
Glycogenesis: liver and muscle
+ -
Glycogenolysis: liver - +
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Process Insulin Glucagon
Lipogenesis: liver and adipose tissue
+ -
Lipolysis: adipose tissue - +/-
Ketogenesis: liver - +
Amino acid uptake: muscle + 0
Protein synthesis + 0
Processes affected by insulin and glucagon
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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 ketosis
Disordered plasma glucose 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
PREDIABETES IFG or IGT
2-h PG > 200 2-h PG 140 199 (IGT)
2-h PG < 140
FPG > 126
FPG > 100 125 (IFG)
FPG < 100
DIABETES NORMAL
A1c > 6.5% A1c 5.7 6.4%
A1c < 5.7%
American Diabetes Association. Diabetes Care 323(Suppl 1), 2009 37
NGSP : National Glycohemoglobin Standardization Program *In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing
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Screening for and diagnosis of GDM
DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 38
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Adapt de Weyer, et al. J Clin Invest. 1999; Ward, et al. Diabetes Care. 1984.
Pathogenesis of type 2 Diabetes
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Duration (minutes)
1st phase 2 nd phase
I.V. Glucose
Diabetes
Normal glucose tolerance
-5 -10 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 100 95
insu
lin S
ecr
etio
n
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Natural History of Type 2 Diabetes
Years
Glu
co
se
(mg
/dL
)
Rela
tive F
un
cti
on
( c
ell
)
-10 -5 0 5 10 15 20 25 30
50
100
150
200
250
300
350
Insulin resistance
Insulin level
Fasting glucose
Post-meal glucose
Onset
Diabetes
Pre-diabetes
metabolic syndrome
0
50
100
150
200
250
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Incretin action
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. 40