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Pro-Insulin
Dr. Mohammed Kalimi
And
Release of Insulin
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Blood glucose
Glucose transport into β cells of pancreas
Glucose transporter proteins
Glucose oxidation
ATP production
Closure of potassium channels
↑ Intracellular calcium
↑ Release of insulin by exocytosis
Diabetes Mellitus
 ↑ Plasma glucose
 Large amount of sweet urine
 Boils and tendency to die in coma
 1889: Minkowsky: Presence of
hypoglycemic factor in pancreas
 1922: Benting and Best- Discovery of

insulin
 1959: Sanger: Chemical analysis of insulin
(51 amino acids peptide)
 1967: Steiner: Proinsulin
 1977: Rosalyn Yalow: Development of Radio
Immuno Assay (RIA)
 Human insulin production by recombinant DNA
technique
 Down regulation of insulin receptor
 Insulin receptor has intrinsic tyrosine phospho kinase
activity
 Insulin pumps (including nasal spray)
 Stem cell research
Insulin release
 ↑ Blood glucose (hyperglycemia)
 ↑ Plasma amino acids (lysine, arginine)
 Diet
 Vagus stimulation: acetylcholine
 Sulfonylureas (hypoglycemic agent)
 GIP and GLP-1 (glucagon-like peptide I)
Insulin Inhibition
 Somatostatin
 Catecholamines
 Fasting
 Exercise
 Leptin
↑Insulin
  Glucose
  Amino acids
  FFA
  Ketoacids
↑ Glucose transport, FFA transport, Amino acids
transport
↑ Cell growth (RNA, DNA and protein synthesis),
Differentiation
Insulin Mechanism
Insulin – Receptor Complex

p- IRS
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PI-3 kinase G-Ras
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MAPK
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Gene Expression
Excess Insulin
 Tumors of β cells
 Hypoglycemia during fasting
 Fasting releases catecholamines
 Rapid heart rate, sweating, hunger and nervousness
 Coma, brain damage
Primary Diabetes
 Type I (Juvenile)
 Type II (Adult onset)
 Diabetes during pregnancy
Diabetes Type I
 10% of all people
 Thin, young, ketosis prone
 Acute onset often with ketosis
 Sensitivity to exogenous insulin
 Destruction of pacreatic β cells
Symptoms of Type I Diabetes
 Increased Hunger
 Increased Thirst
 Frequent Urination
 Fatique
 Weight Loss (negative nitrogen balance)
Type II Diabetes
 Adult , often linked with obesity, hypertension,
dyslipidemia, aging sedentary life style or genomic
predisposition
 Defects in insulin secretion and action (defective
insulin receptor or post receptor defect)
 Increased glucose output from the liver
Symptoms and complications of Type II
Diabetes
 Peripheral insulin resistance
 Increased hunger (polyphagia), Increased thirst
(polydispia), frequent urination
 Frequent infections, cataract and blindness, numbness
or tingling in hands and feet ( amputations),
neuropathy, retinopathy and vascular diseases
 Problems with pregnancy
 Impotence
Secondary Diabetes
Thyrotoxicosis
Acromegaly
Cushing’s syndrome
Destruction of pancreas
Contributions of diabetogenic
hormones
 Effects of hypophysectomy
  Plasma ACTH and glucocorticoid
secretion,symptoms of diabetes
 Effects of pituitary extracts and glucocorticoids,↑
symptoms of diabetes
Methods of Inducing Diabetes
 Anti-insulin serum
 Alloxan and Streptozotocin
 Pancreatectomy
 Viral infection (coxsackie, mumps)
Glucagon
 ↑ Glycogenolysis
 ↑ Gluconeogenesis
 ↑ Lipolysis
Blood
Glucagon
Insulin
↑ Glucose
↑ FFA
↑ Ketoacids
 Aminoacids
 Glucose
 FFA
 Ketoacids
 Aminoacids
Glucagon Release
 Hypoglycemia
 ↑ Plasma amino acids
 Stress and exercise
Glucagon Inhibition
 Somatostatin
 Insulin
 ↑ Blood glucose (hyperglycemia)
 ↑ Blood FFA
Tumors of α Cells
 Excess Glucagon Levels
 Weight loss
 ↑ Plasma glucose, FFA, and ketoacids and  Plasma
amino acids
Somatostatin Release
 ↑ Plasma glucose, amino acids, FFA and GI hormones