EM Savoeun, MD ICU Medical (KSFH)

Endocrine PANCREAS Physiology

References

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

Screening for and diagnosis of GDM

DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 38

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

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

-15

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