Current Diagnosis and Mechanisms of Glucose Dysregulation

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Current Diagnosis and Mechanisms of Glucose
Dysregulation

• Dr. Josephine Carlos-Raboca
• Chief, Section of Endocrinology, Diabetes
  Metabolism
• Makati Medical Center
• Immediate Past President, PSEM

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Outline

• Overview of glucose regulation
• Stages of Dysglycemia (glucose dysregulation)
• Current Diagnostic Criteria for dysglycemia
• Mechanisms of Glucose Dysregulation
• Summary

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Glucose Metabolism

• Tightly regulated to maintain adequate plasma
  levels
• Major hormones
• insulin
• glucagon
• incretins
• Major organs
• islet cells of pancreas
• insulin sensitive organs liver, muscle, fat
• intestines
• Kidneys
• Modulator
• Endocannabinoid System

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Islet as an Organ

• Role of Pancreatic Islets in Normal
• Glucose Homeostasis

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Islet of Langerhans
Micrograph Lelio Orci, Geneva
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Beta and Alpha Cells in the Pancreas of Normal
Individuals
Beta Cells Alpha Cells
Comprise about 50 of the endocrine mass of the pancreas1 Comprise about 35 of the endocrine mass of the pancreas1
Produce insulin and amylin2 Produce glucagon2
Insulin released in response to elevated blood glucose levels2 Glucagon released in response to low blood glucose levels2 leading to increase in glucose
1. Cabrera O et al. PNAS. 200610323342339. 2.
Cleaver O et al. In Joslins Diabetes Mellitus.
Lippincott Williams Wilkins 20052139.
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Insulin Production

• Primary regulators for insulin biosynthesis
• glucose
• glucagon
• incretins- GLP-1, GIP
• Inhibits insulin biosynthesis
• catecholamine
• somatostatin

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Glucagon

• Main regulator- glucose
• amino acids
• incretins
• Insulin
• fatty acids
• ketones

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Insulin and Glucagon Regulate Normal Glucose
Homeostasis
Glucagon (Alpha cell)
Pancreas
()
Insulin (Beta cell)
Glucose uptake
Glucose output
Blood glucose
Muscle and adipose tissue
Porte D Jr et al. Clin Invest Med.
199518247254. Adapted from Kahn CR, Saltiel
AR. Joslins Diabetes Mellitus. 14th ed.
Lippincott Williams Wilkins 2005145168.
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GUT and GUT Hormones

• Na ATP channels absorption of glucose
• Incretins

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Incretins Regulate Glucose Homeostasis Through
Effects on Islet-Cell Function
Ingestion of food

• ? Insulinin glucose-dependent way
• from ß cells(GLP-1 and GIP)

Increased peripheral glucose uptake
Release of incretin gut hormones
GI tract
Pancreas
? INSULIN
? Bloodglucose control
Bloodglucose control
ß cells
a cells
Active GLP-1 and GIP
? GLUCAGON
Decreasedhepatic glucose output
? Glucagon in glucose- dependent way from a
cells (GLP-1)
InactiveGLP-1 (9-36) and GIP (3-42)
Adapted from Brubaker PL, Drucker DJ.
Endocrinology. 20041452653-2659Zander M et al.
Lancet. 2002359824-830 Ahrén B. Curr Diab Rep.
20033365-372 Buse JB et al. In Larsen PR et
al, eds. Williams Textbook of Endocrinology.
10th ed. Philadelphia, PA Saunders
20031427-1483.
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The endocannabinoid system is a modulatory system

• Endocannabinoids
• Synthesized on demand from lipid precursors in
  postsynaptic cell
• CB1 receptors
• Play a key role in energy balance and lipid and
  glucose metabolism

Di Marzo V et al, 2005 Di Marzo V et al,
1998 Wilson R et al, 2002
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Central and peripheral targets of the
endocannabinoid system
HDL high-density lipoprotein
Bensaid M et al, 2003 Pagotto U et al, 2005
Osei-Hyiaman D et al, 2005 Di Marzo V et al,
2005 Liu YL et al, 2005
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Regulation of glucose Homeostasis

• Na dependent transporters in proximal tubules of
  kidneys cotransport glucose with sodium
  maintained by Na/K-ATPase ion pump

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Glucose homeostasis

• Is a balance of glucose appearance and
  disappearance
• Glucose appearance
• endogenous glucose production (liver,
  muscle and kidneys)
• exogenous sources (GIT) affected by
  feeding signals
• Glucose disappearance
• peripheral uptake from liver, muscle and
  fat

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• Current Diagnosis of
• Prediabetes and Diabetes

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Definition of Diabetes

• A metabolic dysregulation
• Hallmark hyperglycemia
• Basic defects
• Islet cell dysfunction
• Insulin insensitivity
• Impaired action of insulin on target tissues

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Definition of Diabetes

• Chronic hyperglycaemia associated with long-term
  damage to
• Eyes
• Kidneys
• Nerves
• Heart and blood vessels

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Hyperglycemia
Stages
Diabetes Mellitus
Impaired Glucose Tolerance or Impaired Fasting
Glucose (Pre-Diabetes)
Normal Glucose Regulation
Type
Not insulin requiring
Insulin requiring for control
Insulin requiring for survival
Type 1
Type 2
Other Specific Type
Gestational Diabetes
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Diagnostic Criteria For DM
FPG 2 hours PG (after 75 g OGTT)
NORMOGLYCEMIA lt 110 mg/dL lt 140mg/dL(7.8mmol/l)
IMPAIRED FASTING GLYCEMIA (IFG) ? 110 and lt 126 mg/dL ---
IMPAIRED GLUCOSE TOLERANCE (IGT) --- ? 140mg/dl(7.8mmol/l) and lt 200 mg/dL(11.1mmol/l)
DIABETES MELLITUS ? 126 mg/dL(7.0 mmol/l) ? 200 mg/dL (11.1mmol/l)
DIABETES MELLITUS Symptoms of diabetes and casual plasma glucose of ? 200 mg/dl(11.1mmol/l) Symptoms of diabetes and casual plasma glucose of ? 200 mg/dl(11.1mmol/l)
lt100mg/dL (5.6mmol/l)
?100mg/dl(5.6mmol) andlt 126 mg/dL(7.0)
American Diabetes Association 2003
ADA, Diabetes Care 2009
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Hba1c

• Integrated summary of circadian blood glucose in
  the preceding 6-8 weeks
• Not used as diagnostic test for diabetes
• Lack of standardized analytical method and
  therefore lack of a uniform non diabetic
  reference level between laboratories
• Insensitive in the low range
• Normal aic cannot exclude diabetes or IGT

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Issues on current diagnostic cut off

• 3 studies on which FPG of 7.0 cutoff was based
  for diagnosis of diabetes used direct
  ophthalmoscopic examination and one retinal
  photograph
• Diabetes Prevention Program showed substantial
  prevalence of retinopathy below FPG of 7.0
• Cardiovascular complications occur at lower
  glucose levels
• Definition and classification of diabetes and pre
  states should be based on the level of subsequent
  risk of cardiovascular complications class 1
  level B ESC,EASD 2007

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Relation between FPG and retinopathy

• BMES AusDiab MESA
• FPG 5.3 6.5
  5.9
• (Mean)
• Number 364 210
  959
• () with (11.5) (9.3)
  (15.8) Retinopathy
• Lancet 2008

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Blue Mountains Eye Study (5-year incident
retinopathy)
Any retinopathy
Percentage
Fasting plasma glucose (mmol/L)
Number with any retinopathy 40 100 24 12 3 7 3 2 5
Total 545 996 241 56 21 15 9 5 15
Relation between baseline FPG and incident
retinopathy, BMES
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Recommendation

• Current diagnostic criteria remain the best
• tools for now.

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Mechanisms of Glucose Dysregulation and
Development of Type 2 Diabetes
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Genetics

• 39 of patients with type 2 diabetes have at
  least one parent with the disease
• Among monozyzgotic twin pairs with one affected
  twin, approximately 90 of unaffected twins
  eventually develop the disease
• First degree relative of patients with type 2
  diabetes frequently have impaired nonoxidative
  glucose metabolism long before they develop type
  2 diabetes
• Ethnic predilection

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Environment

• Low birth weight
• Gestational diabetes
• Prematurity
• Sedentary lifestyle
• High fat diet

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Physiologic Molecular basis of Diabetes

• Physiologic
• islet cell dysfunction
• insulin resistance
• Molecular
• insulin receptor
• Insulin signal transduction

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Beta-Cell Function Is Abnormal in Type 2 Diabetes

• A range of functional abnormalities is present
• Abnormal oscillatory insulin release
• Increased proinsulin levels
• Abnormal insulin response
• Progressive loss of beta-cell functional mass

Adapted from Buchanan TA Clin Ther 200325(suppl
B)B32B46 Polonsky KS et al N Engl J Med
198831812311239 Quddusi S et al Diabetes Care
200326791798 Porte D Jr, Kahn SE Diabetes
200150(suppl 1)S160S163.
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First-Phase Insulin Response to IV Glucose Is
Lost in Type 2 Diabetes
Normal
Type 2 Diabetes
120
120
100
100
80
80
Plasma insulin (µU/mL)
Plasma insulin (µU/mL)
60
60
40
40
20
20
0
0
30
0
30
60
90
120
30
0
30
60
90
120
Time (min)
Time (min)
n9 normal n9 type 2 diabetes. Adapted from
Pfeifer MA et al. Am J Med. 198170579588.
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Fewer Pancreatic Islets in Type 2 Diabetes
Adapted from Rhodes CJ. Science. 2005307380384.
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Increased Beta-Cell Apoptosis Occurs in Type 2
Diabetes

plt0.05. Islet cell death was assessed by an
ELISA method, which evaluates the cytoplasmic
histone-associated DNA fragments. After
incubation absorbance of samples was read
spectrophotometrically. Data obtained from
pancreatic islets isolated from 6 T2DM organ
donors and 10 nondiabetic cadaveric organ
donors. Adapted from Marchetti P et al. J Clin
Endocrinol Metab. 20048955355541.
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Amylin

• Amylin co-secreted with insulin
• Low amylin levels in type 2 diabetes
• cause or effect is unclear

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Insulin and Glucagon Response to a Large
Carbohydrate Meal in Type 2 Diabetes
Type 2 diabetes mellitus (n12) Nondiabetic
controls (n11)
360
330
Meal
300
Glucose (mg/100 ml)
270
240
110
80
150
120
Insulin (µU/ml)
90
60
30
0
140
130
Glucagon (µµg/ml)
120
110
100
90
60
0
60
120
180
240
Time (minutes)
Insulin measured in five patients Adapted from
Müller WA et al N Engl J Med 1970283109115.
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Incretin Function in Type 2 Diabetes

• Secretion of GLP-1 impaired
• Beta-cell sensitivity to GLP-1 decreased
• Secretion of GIP normal (or slightly impaired)
• Effect of GIP abolished or grossly impaired

Toft-Nielsen M-B et al. J Clin Endocrinol Metab.
20018637173723 Kjems LL et al. Diabetes.
200352380386 Vilsbøll T et al. Diabetologia.
20024511111119 Vilsbøll T et al. J Clin
Endocrinol Metab. 20038848974903.
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The Pathophysiology of Type 2 Diabetes Includes
Islet Cell Dysfunction and Insulin Resistance
Glucagon (Alpha cell)
Pancreas
Insulin (Beta cell)
Glucose uptake
Glucose output
Hyperglycemia
Muscle and adipose tissue
Buse JB et al. In Williams Textbook of
Endocrinology. 10th ed. Saunders, 200314271483
Buchanan TA. Clin Ther. 200325(suppl
B)B32B46 Powers AC. In Harrisons Principles
of Internal Medicine. 16th ed. McGraw-Hill,
200521522180 Rhodes CJ. Science.
2005307380384. Adapted from Kahn CR, Saltiel
AR. Joslins Diabetes Mellitus. 14th ed.
Lippincott Williams Wilkins 2005145168.
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Insulin Resistance

• Genetics
• Age
• Weight
• adipokines

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Intra-abdominal adiposity is a major contributor
to insulin resistance
IAA high risk fat
Dyslipidaemia
DM2 Increased cardiometabolic risk
Insulin resistance
Inflammation
IAA intra-abdominal adiposity
Kershaw EE et al, 2004 Lee YH et al, 2005
Boden G et al, 2002
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endocannabinoid system dysregulation
Weight-dependent
Weight Independent
Endocannabinoid system
ECS
Modified from Lam TKT, 2003 Carr DB, 2004
Eckel R, 2005 Pagotto U, 2005 Di Marzo V et
al, 2005
FFAfree fatty acids CETPcholesterol ester
transfer protein
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Insulin Action

• decrease in number of insulin receptors
• any disruption in the transcription or
  transduction of insulin signaling pathway

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Summary

• Glucose metabolism is tightly regulated to
  maintain desirable glucose levels
• Glucose dysregulation leads to progressive
  dysglycemia from prediabetes to frank diabetes
• The pathophysiology of type 2 diabetes is
  complex.
• Involves multiple physiologic and molecular
  disturbances influenced by multiple genes and
  environmental factors
• This offers multiple target sites for therapy and
  explains the complexity of treatment of DM2