3. Normal Glucose Homeostasis
REGULATED BY:
1. Glucose production in the liver
2. Glucose uptake and utilization by peripheral tissues
(skeletal muscle)
3. Actions of hormones
Normal glucose levels: 70-120mg/dl
• FXN of Insulin: to increase the rate of glucose transport
into certain cells of the body
4. Glucose Metabolism: Words you need to know!
• Gluconeogenesis: formation of glucose from excess amino acids,
fat, and other noncarbohydrate sources.
• Glycogenesis: formation of glycogen.
• Lipogenesis: formation of fats
• Glycogenolysis: process that coverts glycogen to glucose.
• Glycolysis: hydrolysis of glucose to pyruvate.
• Lipolysis: catabolic degradation of triacylglycerol.
5. Glucose Metabolism
Synthesis of glycogen Breaking down stored glycogen
Production of glucose
from a.a. & other
substances
Cellular
Respiration
6. PANCREAS
Exocrine
Endocrine
Islets
Alpha Cells glucagon
Beta Cells proinsulin
Delta Cells somatostatin
(suppress insulin and glucagon)
F cells Pancreatic Polypeptide
(PP) cells
Epsilon Cells make gherlin, which
causes hunger
8. Regulation of Glucose Metabolism
• HORMONAL REGULATION
• Glucose–dependent insulinotropic
polypeptide (GIP)
• Glucagon-like peptide 1 (GLP-1)
– from cells in the gut
– stimulate the production of insulin and inhibit
glucagon
12. Metabolic
Action of
Insulin
Liver Adipose Muscle
Inhibits Glycogenolysis Lipolysis Protein break down
Gluconeogenesis Amino acid release
Ketogeneis
Simulates Glycogen fatty acid Glycerol and fatty acid Glucose uptake and
synthesis synthesis metabolism
Amino acid uptake
Synthesis of protein
Glycogenesis
13. Fed State Fasting State
Glucose provides primary energy source Glucose is produced by
Amylin acts on area postrema (AP) glycogenolysis and gluconeogenesis
INSULIN dominated GLUCAGON dominates
14. Regulation of Glucose Metabolism
• EXERCISE
– Initially insulin levels
drop and glucagon and
catecholamine levels rise
• STRESS
– Production of stress
hormones
(corticosteroids and
catecholamines) increase
production of glucose
– Increase production of
FFAs
– Lead to hyperglycemia
16. Who has Diabetes Mellitus
• 16 Million in the USA
• 1 Million/yr
• 50K people die of it per year in the USA
17. What is diabetes mellitus?
• GLUCOSE INTOLERANCE
• How do you diagnose DM?
• More than one fasting plasma glucose level
(>126)
• Elevated plasma glucose in response to an oral
glucose tolerance test (>200)
• Polydipsia, polyphagia, polyuria
18.
19. * MODY might be regarded
as the third type
TWO* Types of DM
Type 1 Type 2
• Genetic • Genetic, but diff. from Type
• Autoimmune 1
• Childhood (juvenile) • NOT autoimmune
onset • Adult, or maturity onset,
• Antibodies to beta cells, e.g., 40’s, 50’s
insulitis • Insulin may be low, BUT,
peripheral resistance to
• Beta cell depletion
insulin is the main factor
• NON-OBESE patients
• OBESE patients
22. Pathogenesis of Diabetes Mellitus
• HLAs: expression of certain HLAs is associated with increased
susceptibility to type I diabetes.
• Viruses: are considered initiating factors in autoimmune
cause of type I diabetes.
• Insulin receptor defects:
Insulin resistant: can be due to malfunction in insulin receptor, but the
cause is not known. In type II diabetes.
Antibodies to insulin receptor: in type II diabetes.
• Glucose transport: low levels of glucose transporters in type I
and II diabetes.
23. Pathogenesis of Diabetes Mellitus
• Type I diabetes mellitus: caused by destruction of
islet cells as a result of autoimmune reaction to -
cells.
• Type II diabetes mellitus: caused by a defect in
glucose transport after insulin binds to its receptor.
24. Type 1 DM
Genetic susceptibility
Environmental factors
Immunologically mediated destruction of beta cells
Peak about 10-14 years of age
25. • A 12-year-old female is newly diagnosed with
type 1 diabetes mellitus (DM). Which of the
following is the most likely cause of her
disease?
A. A familial, autosomal dominant gene defect
B. Obesity and lack of exercise
C. Immune destruction of the pancreas
D. Hyperglycemia from eating too many sweets
28. Type 2 DM
• RESISTANT TO THE ACTION OF INSULIN
• Very common: many undiagnosed cases
• Interactions of metabolic, genetic, &
environment
• RISK FACTORS: high BMI (intra-abdominal
obesity), family history of DM2, ethnic
minority, female gender
29. • Insulin is less able to facilitate entry of
glucose into live, skeletal muscles, adipose
tissue
• Pancreas eventually “burns out”
31. MODY (Maturity Onset Diabetes of
the Young)
• Multiple types
• 2-5% of diabetics
• Primary beta cell defects
• Multiple genetic mechanisms, especially
GLUCOKINASE mutations
32. Hyperglycemia in type 2 diabetes mellitus is a
result of:
A. insulin deficiency.
B. hyperinsulinemia and insulin resistance.
C. glucagon deficiency.
D. liver dysfunction.
40. Acute Complications: Diabetic ketoacidosis
Insulinopenia (in type I diabetes)
Use of fatty acids from triglycerides as a major source of energy
Fatty acid degradation
Production of acetyl CoA
Production of keto acids (ketone bodies)
(acetoacetate, -hydroxybutyrate)
42. A 19-year-old female with type 1 diabetes mellitus was
admitted to the hospital with the following lab values: serum
glucose 500 mg/dl (high); urine glucose and ketones 4+
(high); arterial pH 7.20 (low). Her parents state that she has
been sick with the “flu” for a week. Which of the following
statements best explains her acidotic state?
A. Increased insulin levels promote protein breakdown and
ketone formation.
B. Her uncontrolled diabetes has led to renal failure.
C. Low serum insulin promotes lipid storage and a
corresponding release of ketones.
D. Insulin deficiency promotes lipid metabolism and ketone
formation.
43. Acute Complications Protein glycation
• Nonenzymatic binding of free amino groups of
proteins to glucose and other sugars.
• Protein glycation commonly occurs in RBCs,
glumeruli, nerve cells, and other tissues.
• Extent of protein glycation is proportional to
extracellular glucose concentration.
• Excessive glycation causes alterations in
protein’s physical and biochemical properties.
• New research suggest that many diabetes
complications are caused by glycation of
specific proteins.
44. Diagnostic Tests for Diabetes Mellitus
Function tests in diabetes
• Postprandial plasma glucose
• Oral glucose tolerance test
Other tests in diabetes
• Glucose
• Glycated hemoglobin
• Albumin (protein)
• Insulin
• Keto acids
• Hydrogen ion
• Electrolytes
• Osmolality
• Body fluid volume
• Anion gap
• BUN
• Lipids
45. Function tests in diabetes
Both tests measure clearance rate of glucose load from the
blood.
Postprandial plasma glucose:
• A high in carbohydrate meal is used (75 g glucose drink is preferred) as
carbohydrate load.
• Plasma glucose is measured 2 hours after carbohydrate ingestion.
• Two postprandial tests with glucose levels 200 mg/dl are suggestive of diabetes.
Oral glucose tolerance test (OGTT): under controlled conditions.
• Carbohydrate intake is controlled 3 days before the test.
• Glucose load is 40 g glucose/m2 body area.
• Blood glucose is measured 2 hours after glucose load.
• Glucose level 200 mg/dl is suggestive of diabetes.
46. Glucose
Fasting plasma glucose:
• Repeated levels 126 mg/dl…strongly suggest diabetes.
• Levels 100 – 126 mg/dl …impaired fasting glucose.
• Increase in fasting plasma glucose is directly proportional to
severity of diabetes mellitus.
Urinary glucose:
• Renal threshold for glucose is 180 g/dl, and in diabetics it is
increased to 300 mg/dl.
Urinary glucose is a poor marker for diabetes mellitus.
47. Insulin
• Type I diabetics: fasting plasma insulin is low.
• Type II diabetics: fasting plasma insulin is normal, it is
high if plasma glucose 250 mg/dl
48. Keto acids
• Measured in both blood and urine.
• Plasma keto acids may be normal even though urinary
keto acids are high, this is due to increase urinary
excretion of keto acids from renal compensation to low
pH.
• Controlled diabetics should have both normal plasma
and urinary keto acid levels.
49. Albumin
• Urinary protein (microalbuminuria) is one of the
earliest signs of glomerular nephropathy.
• Albumin / creatinine 20-30 mg/day suggests
microalbuminuria.
• Without intervention macroalbuminuria
(>300mg/day)
– Leading cause of end stage renal disease in US
