Transcript Glucose homeostasis, Pathophysiology of diabetes & ADA

Glucose homeostasis,
pathophysiology of diabetes
& ADA Guidelines
JC Lynch
PHPT 726
2007
Glucose homeostasis
Glycogenolysis & Glucoeogenesis
Hepatic Glucose Output

Glycogenolysis
– Catabolism of
glycogen.

Gluconeogenesis
– Production of glucose
from carbohydrates or
proteins.
(this is the simple slide: know this first)
Comparison of normal glucose patterns to patient with
diabetes (probably type 1).
Direct Effects of Insulin
Glucose metabolism
 Lipoprotein metabolism
 Ketone metabolism
 Protein metabolism

Insulin Action: Definitions
Insulin Sensitivity
 Ability
of insulin to lower circulating
glucose concentrations
Insulin Resistance
 Condition
of low insulin sensitivity
Glucose Metabolism
Major Metabolic
Effects of Insulin
Stimulates
glucose
uptake into muscle
and adipose cells
Inhibits hepatic
glucose production
Consequences of
Insulin Deficiency
Hyperglycemia
osmotic diuresis and
dehydration
Lipoprotein Metabolism
Major Metabolic
Effects of Insulin
Consequences of
Insulin Deficiency
Inhibits
Elevated
breakdown
of triglycerides
(lipolysis) in adipose
tissue
FFA levels
Ketone Metabolism
Major Metabolic
Effects of Insulin
Inhibits
ketogenesis
Ketogenesis:
is the
process by which
ketone bodies are
produced as a result of
fatty acid breakdown.
Consequences of
Insulin Deficiency
Ketoacidosis
Protein Metabolism
Major Metabolic
Effects of Insulin
Stimulates
amino
acid uptake and
protein synthesis
Inhibits protein
degradation
Regulates gene
transcription
Consequences of
Insulin Deficiency
Muscle
Others
wasting
Insulin and Amylin Co-secreted
Meal Meal Meal
30
Plasma amylin (pM)
Without Diabetes
n=6
20
400
15
200
10
5
0
7 am
12 noon
5 pm
Time
Koda et al, Diabetes. 1995; 44 (s1): 23BA.
Data on file. (Fineman)
Midnight
Plasma insulin (pM)
600
25
Insulin
Amylin
Amylin
Secreted by pancreatic beta-cells
 An anorectic hormone
 Works on the brain to stimulate the feeling
of satiety.
 This results in decreased G.I. motility,
slowed carbohydrate absorption, and
decreased appetite.

GLP-1
“Incretin” hormone secreted by jejunal
and ileal L cells in response to a meal
 Stimulates insulin secretion
 Decreases glucagon secretion
 Slows gastric emptying
 Reduces fuel intake (increases satiety)
 Improves insulin sensitivity
 Increases b-cell mass and improves bcell function (animal studies)

GLP-1 release following meal:
comparison of control, T2DM & IGT
Diabetes
Pathophysiology
Diabetes is a
Multi-Hormonal Disease

Pancreatic hormones
– Insulin (b-cell)
– Glucagon (a-cell)
– Amylin (b-cell)

Intestinal Hormones (Incretins)
– GLP-1 (L-cells)
– GIP (K-cells)
Type 1 Diabetes:
Pathophysiology
 Impaired insulin secretion
– Absolute insulin deficiency
T1DM
Typically autoimmune (~90%)
 Beta-cells destroyed by multiple antibodies.
 Can occur at any age (but more in kids)
 Fast progression (the older the slower)
 Related to ketones @

– Urine ketones
– Ketoacidosis
 Weight loss, N&V, lethargy
Ketogenesis
Normal physiological responses to
carbohydrate shortages cause the liver to
increase the production of ketone bodies
from the acetyl-CoA generated from fatty
acid oxidation.
 Allows the heart and skeletal muscles
primarily to use ketone bodies for energy,
thereby preserving the limited glucose for
use by the brain

Honeymooning
The ability of the failing b-cells to become
hyper-productive and compensate for failing
insulin response.
T2DM
Diagnosis characteristics
Insidious
 Obesity (almost always), or weight gain
 Related to other IRS signs

– Hyperlipidemia, acanthosis nigricans
Older (↑Obesity = ↓Age; fatter = younger)
 Ethnic links
 Family history of T2DM
 No ketones

Acanthosis Nigricans
Hyperpigmented,
velvety patches of skin
in axillary regions and
neck (typically).
Type 2 Diabetes:
Pathophysiology
 Impaired insulin secretion
– Absolute or relative insulin deficiency
 Impaired
insulin action
(sensitivity)
– Insulin resistance
Dual Metabolic Abnormalities in
Type 2 Diabetes
Insulin Resistance
Decreased
Glucose Uptake
Unrestrained
Lipolysis
Excessive
Hepatic
Glucose
Output
Insulin Deficiency
Decreased
Insulin
Secretion
Natural History of T2DM
Obesity
IGT* Diabetes
Symptomatic
Hyperglycemia
Post-meal
Glucose
Plasma
Glucose
Fasting Glucose
120 (mg/dL)
Insulin Resistance
Relative b-Cell
Function
Diabetes
100 (%)
-20
*IGT = impaired glucose tolerance
-10
0
10
Years of Diabetes
20
30
Insulin Resistance Syndrome
(Metabolic Syndrome)
Glucose
Intolerance
Dyslipidemia
Hypertension
Insulin
Resistance
PCOS
Obesity
(High TG, Low HDL)
Cardiovascular
Disease
Response to Insulin Resistance:
The Pancreatic b Cell (early T2DM)
Genes
C
Environment
INSULIN RESISTANCE
Normal
b cells
Hyperinsulinemia
(normal glucose)
Abnormal
b cells
Hyperglycemia
(relative insulin deficiency)
Hepatic Insulin Resistance
(T2DM)
Hepatic glucose output
(µmol/kg/min)
25
20
Glycogenolysis
15
10
5
Gluconeogenesis
0
CON
T2DM
Adapted from Consoli A. Diabetes 1989;38:550–557.
Relative Organ Contribution to
Decreased Glucose Uptake
7
6
5
Adipose
Splachnic
4
Muscle
3
2
1
Brain
0
Control
T2DM
Adapted from DeFronzo RA. Diabetes 1988;37:667–687.
Insulin Resistance:
Inherited and Acquired Influences
Inherited
Rare Mutations
 Insulin receptor
 Glucose transporter
 Signalling proteins
Common Forms
 Largely unidentified
C
Acquired






INSULIN RESISTANCE
Inactivity
Obesity
Stress
Medications
Glucose toxicity
Lipotoxicity
Agent
Target
Site(s) of action
Insulins/Analogues
Insulin receptor
Liver, muscle, fat
Sulfonylureas
Phenylalanine Der.
Meglitinides
SFU receptor
K-ATP Channel
Pancreatic b cell
Metormin
Unknown
Liver (muscle)
Glucosidase inhibitors
a-glucosidase
Intestine
Thiazolidinediones
PPAR-g
Muscle (liver, fat)
Exenatide
GLP-1 receptors
Pancreas
Vildagliptin
DPP 4 (inhibition)
Enzymatic
Atypical diabetes
Idiopathic type 1 diabetes
Also known as “Flatbush diabetes”
 African American and Asian men (18-25)
 Fluctuating insulin secretion
 No antibodies
 Many honeymoons

LADA
Latent autoimmune diabetes of adulthood
 Like type 1 but diagnosed after age 25.
 ~20% of those with diagnosis of T2 may
actually have LADA.
 Slower onset than type 1 dm.
 Positive antibodies.
 Low or no c-peptide
 No family history

MODY
Maturity Onset Diabetes of the Young
 A collection of many (at least 6) inherited
diseases affecting insulin secretion.
 Dominant inheritance characteristics
 Normal insulin sensitivity
 Impaired insulin secretion (but still some).
 Diagnosis confirmed by genetic testing.

Pancreatic Diabetes
Results from a failure of the pancreas as a
whole.
 May be secondary to ETOH abuse, trauma,
repeat pancreatitis.
 Exocrine pancreas generally fails before
endocrine pancreas.
 Will need pancreatic enzyme replacement
as well as insulin.

Gestational diabetes

Any glucose intolerance first diagnosed
during pregnancy
– Some definitions require return to normal
following end of pregnancy.
Closely related to T2DM
 Treat only with insulin

– Some data support the use of SUs &
metformin.
Diagnosis of GDM with a 100-g oral glucose load
Fasting
1-h
2-h
3-h
mg/dl
mmol/l
95
180
155
140
5.3
10.0
8.6
7.8
A1C monitoring
A1c (%)
6
Mean Plasma glucose mg/dl
135
7
170
8
205
9
240
10
275
11
310
12
345
For every 1% point
of increase in A1c
add 35mg/dl of
glucose.
False A1C Readings

Elevated
– Iron deficiency anemia
– Splenectomy

Decreased
– Hemolytic anemia
– Sickle cell anemia
– Transfusion
ADA Guidelines
http://www.diabetes.org/
Case #1