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Glucose homeostasis, pathophysiology of diabetes & ADA Guidelines

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Glucose homeostasis, pathophysiology of diabetes & ADA Guidelines JC Lynch PHPT 726 2007 Glucose homeostasis Glycogenolysis & Glucoeogenesis Hepatic Glucose Output ... – PowerPoint PPT presentation

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Title: Glucose homeostasis, pathophysiology of diabetes & ADA Guidelines


1
Glucose homeostasis, pathophysiology of diabetes
ADA Guidelines
  • JC Lynch
  • PHPT 726
  • 2007

2
Glucose homeostasis
3
Glycogenolysis GlucoeogenesisHepatic Glucose
Output
  • Glycogenolysis
  • Catabolism of glycogen.
  • Gluconeogenesis
  • Production of glucose from carbohydrates or
    proteins.

4
(this is the simple slide know this first)
5
Comparison of normal glucose patterns to patient
with diabetes (probably type 1).
6
Direct Effects of Insulin
  • Glucose metabolism
  • Lipoprotein metabolism
  • Ketone metabolism
  • Protein metabolism

7
Insulin Action Definitions
  • Insulin Sensitivity
  • Ability of insulin to lower circulating glucose
    concentrations
  • Insulin Resistance
  • Condition of low insulin sensitivity

8
Glucose Metabolism
9
Lipoprotein Metabolism
10
Ketone Metabolism
11
Protein Metabolism
12
Insulin and Amylin Co-secreted
Meal
Meal
Meal
30
25
Without Diabetes n 6
Plasma amylin (pM)
Plasma insulin (pM)
20
15
10
5
7 am
Midnight
5 pm
12 noon
Time
Koda et al, Diabetes. 1995 44 (s1) 23BA. Data
on file. (Fineman)
13
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.

14
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 b-cell
    function (animal studies)

15
GLP-1 release following mealcomparison of
control, T2DM IGT
16
(No Transcript)
17
Diabetes Pathophysiology
18
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)

19
Type 1 Diabetes Pathophysiology
  • Impaired insulin secretion
  • Absolute insulin deficiency

20
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 _at_
  • Urine ketones
  • Ketoacidosis
  • Weight loss, NV, lethargy

21
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

22
Honeymooning
  • The ability of the failing b-cells to become
    hyper-productive and compensate for failing
    insulin response.

23
T2DMDiagnosis 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

24
Acanthosis Nigricans
Hyperpigmented, velvety patches of skin in
axillary regions and neck (typically).
25
Type 2 Diabetes Pathophysiology
  • Impaired insulin secretion
  • Absolute or relative insulin deficiency
  • Impaired insulin action (sensitivity)
  • Insulin resistance

26
Dual Metabolic Abnormalities in Type 2 Diabetes
Insulin Resistance
Insulin Deficiency
Decreased Glucose Uptake
Decreased Insulin Secretion
Unrestrained Lipolysis
Excessive Hepatic Glucose Output
27
Natural History of T2DM
Symptomatic Obesity IGT Diabetes
Hyperglycemia
Post-meal Glucose
Plasma Glucose
Fasting Glucose
120 (mg/dL)
Insulin Resistance
Relative ?-Cell Function
Diabetes
100 ()
-20
-10
0
10
20
30
Years of Diabetes
IGT impaired glucose tolerance
28
Insulin Resistance Syndrome (Metabolic Syndrome)
Glucose Intolerance
Dyslipidemia (High TG, Low HDL)
Hypertension
InsulinResistance
PCOS
Cardiovascular Disease
Obesity
29
Response to Insulin ResistanceThe Pancreatic b
Cell (early T2DM)
Environment
Genes
INSULIN RESISTANCE
Normal b cells
Abnormal b cells
Hyperglycemia (relative insulin deficiency)
Hyperinsulinemia (normal glucose)
30
Hepatic Insulin Resistance(T2DM)
25 20 15 10 5 0
Glycogenolysis
Hepatic glucose output (µmol/kg/min)
Gluconeogenesis
CON
T2DM
Adapted from Consoli A. Diabetes 198938550557.
31
Relative Organ Contribution to Decreased Glucose
Uptake
7 6 5 4 3 2 1 0
Splachnic
Adipose
Insulin-stimulated Glucose Uptake (mg/kg/min)
Muscle
Brain
Control
T2DM
Adapted from DeFronzo RA. Diabetes
198837667687.
32
Insulin ResistanceInherited and Acquired
Influences
Acquired
Inherited
Rare Mutations l Insulin receptorl Glucose
transporterl Signalling proteins Common
Forms l Largely unidentified
l Inactivity l Obesity l Stress l
Medications l Glucose toxicity l Lipotoxicity
INSULIN RESISTANCE
33
(No Transcript)
34
Atypical diabetes
35
Idiopathic type 1 diabetes
  • Also known as Flatbush diabetes
  • African American and Asian men (18-25)
  • Fluctuating insulin secretion
  • No antibodies
  • Many honeymoons

36
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

37
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.

38
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.

39
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.

40
Diagnosis of GDM with a 100-g oral glucose load

41
A1C monitoring
42
For every 1 point of increase in A1c add 35mg/dl
of glucose.
43
False A1C Readings
  • Elevated
  • Iron deficiency anemia
  • Splenectomy
  • Decreased
  • Hemolytic anemia
  • Sickle cell anemia
  • Transfusion

44
ADA Guidelines
  • http//www.diabetes.org/

45
Case 1
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