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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. Outline. Overview of glucose regulation Stages of Dysglycemia (glucose dysregulation)

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current diagnosis and mechanisms of glucose dysregulation

Current Diagnosis and Mechanisms of Glucose Dysregulation

Dr. Josephine Carlos-Raboca

Chief, Section of Endocrinology, Diabetes & Metabolism

Makati Medical Center

Immediate Past President, PSEM

outline
Outline
  • Overview of glucose regulation
  • Stages of Dysglycemia (glucose dysregulation)
  • Current Diagnostic Criteria for dysglycemia
  • Mechanisms of Glucose Dysregulation
  • Summary
glucose metabolism
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
islet as an organ

Islet as an Organ:

Role of Pancreatic Islets in Normal

Glucose Homeostasis

islet of langerhans
Islet of Langerhans

~ 3,000 cells

75% Beta cells

25% non-Beta cells

200 µm

Micrograph: Lelio Orci, Geneva

beta and alpha cells in the pancreas of normal individuals
Beta and Alpha Cells in the Pancreas of Normal Individuals

1. Cabrera O et al. PNAS. 2006;103:2334–2339.

2. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21–39.

insulin production
Insulin Production
  • Primary regulators for insulin biosynthesis
    • glucose
    • glucagon
    • incretins- GLP-1, GIP
  • Inhibits insulin biosynthesis
    • catecholamine
    • somatostatin
glucagon
Glucagon
  • Main regulator- glucose

amino acids

    • incretins
    • Insulin
    • fatty acids
    • ketones
insulin and glucagon regulate normal glucose homeostasis
Insulin and Glucagon Regulate Normal Glucose Homeostasis

(–)

(–)

(+)

(–)

(+)

Liver

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. 1995;18:247–254.

Adapted from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

gut and gut hormones
GUT and GUT Hormones
  • Na ATP channels – absorption of glucose
  • Incretins
incretins regulate glucose homeostasis through effects on islet cell function
Incretins Regulate Glucose Homeostasis Through Effects on Islet-Cell Function

Ingestion of food

 Insulinin glucose-dependent way

from β cells(GLP-1 and GIP)

Increased peripheral glucose uptake

Release of incretin gut hormones

GI tract

Pancreas

INSULIN

Bloodglucose control

 Bloodglucose control

β cells

α cells

Active GLP-1 and GIP

↓GLUCAGON

Decreasedhepatic glucose output

 Glucagon

in glucose- dependent way from αcells (GLP-1)

InactiveGLP-1 (9-36)

and GIP (3-42)

Adapted from Brubaker PL, Drucker DJ. Endocrinology. 2004;145:2653-2659;Zander M et al. Lancet. 2002;359:824-830; Ahrén B. Curr Diab Rep. 2003;3:365-372; Buse JB et al. In Larsen PR et al, eds.: Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: Saunders; 2003:1427-1483.

the endocannabinoid system is a modulatory system
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

central and peripheral targets of the endocannabinoid system
Central and peripheral targets of the endocannabinoid system

Brain

Peripheral tissues

Adipose

Liver

Muscle

tissue

GI tract

Hypothalamus:

Nucleus accumbens:

^

^

hunger

motivation to eat

Insulin resistance

^

HDL-cholesterol

Triglycerides

^

Increased food intake

Glucose uptake

Increased fat storage

Adiponectin

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

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

slide17
Current Diagnosis of

Prediabetes and Diabetes

definition of d iabetes
Definition of Diabetes
  • A metabolic dysregulation
  • Hallmark: hyperglycemia
  • Basic defects:
  • Islet cell dysfunction
    • Insulin insensitivity
    • Impaired action of insulin on target tissues
definition of diabetes
Definition of Diabetes
  • Chronic hyperglycaemia associated with long-term damage to:
    • Eyes
    • Kidneys
    • Nerves
    • Heart and blood vessels
slide20

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 **

diagnostic criteria for dm
Diagnostic Criteria For DM

American Diabetes Association 2003

ADA, Diabetes Care 2009

hba1c
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
issues on current diagnostic cut off
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
relation between fpg and retinopathy
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
slide25

Blue Mountains Eye Study (5-year incident retinopathy)

Any retinopathy

Percentage

Fasting plasma glucose (mmol/L)

Relation between baseline FPG and incident retinopathy, BMES

recommendation
Recommendation
  • Current diagnostic criteria remain the best

tools for now.

genetics
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
environment
Environment
  • Low birth weight
  • Gestational diabetes
  • Prematurity
  • Sedentary lifestyle
  • High fat diet
physiologic molecular basis of diabetes
Physiologic & Molecular basis of Diabetes
  • Physiologic

islet cell dysfunction

insulin resistance

  • Molecular

insulin receptor

Insulin signal transduction

beta cell function is abnormal in type 2 diabetes
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 2003;25(suppl B):B32–B46; Polonsky KS et al N Engl J Med 1988;318:1231–1239; Quddusi S et al Diabetes Care 2003;26:791–798; Porte D Jr, Kahn SE Diabetes 2001;50(suppl 1):S160–S163.

first phase insulin response to iv glucose is lost in type 2 diabetes
First-Phase Insulin Response to IV Glucose Is Lost in Type 2 Diabetes

Type 2 Diabetes

Normal

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)

n=9 normal; n=9 type 2 diabetes.

Adapted from Pfeifer MA et al. Am J Med. 1981;70:579–588.

slide33

Normal

Compensation

More islets

Larger islets

More beta cells/islet

Larger beta cells

Nondiabetic Obesity

Decompensation

Fewer islets

Fewer beta cells/islet

Amyloidosis

Type 2 diabetes

Fewer Pancreatic Islets in Type 2 Diabetes

Adapted from Rhodes CJ. Science. 2005;307:380–384.

increased beta cell apoptosis occurs in type 2 diabetes
Increased Beta-Cell Apoptosis Occurs in Type 2 Diabetes

*

*p<0.05. 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. 2004;89:5535–5541.

amylin
Amylin
  • Amylin co-secreted with insulin
  • Low amylin levels in type 2 diabetes
  • cause or effect is unclear
insulin and glucagon response to a large carbohydrate meal in type 2 diabetes
Insulin and Glucagon Response to a Large Carbohydrate Meal in Type 2 Diabetes

Depressed/delayed insulin response

Nonsuppressed glucagon

Type 2 diabetes mellitus (n=12)*

Nondiabetic controls (n=11)

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 1970;283:109–115.

incretin function in type 2 diabetes
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. 2001;86:3717–3723; Kjems LL et al. Diabetes. 2003;52:380–386;

Vilsbøll T et al. Diabetologia. 2002;45:1111–1119; Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88:4897–4903.

the pathophysiology of type 2 diabetes includes islet cell dysfunction and insulin resistance
The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance

Liver

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, 2003:1427–1483; Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. McGraw-Hill, 2005:2152–2180; Rhodes CJ. Science. 2005;307:380–384.

Adapted from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

insulin resistance
Insulin Resistance
  • Genetics
  • Age
  • Weight
  • adipokines
intra abdominal adiposity is a major contributor to insulin resistance
Intra-abdominal adiposity is a major contributor to insulin resistance

Associated with

inflammatory markers

(C-reactive protein)

Free fatty

acids

Secretion of

adipokines

(↓ adiponectin)

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

endocannabinoid system dysregulation
endocannabinoid system dysregulation

Feeding

ECS

CB-1 blockade

Weight

Dyslipidaemia

Type 2 diabetes

Peripheral insulinresistance

Hepatic insulinresistance

Hepaticglucoseoutput

Small,denseLDL-C

LowHDL-C

CETP,lipolysis

Adiponectin

Lipolysis

FFA

TG-richVLDL-C

FFA

Portal circulation

ECS

Liver

Visceral fat

ECS

CB-1 blockade

CB-1 blockade

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

FFA=free fatty acids

CETP=cholesterol

ester transfer protein

insulin action
Insulin Action
  • decrease in number of insulin receptors
  • any disruption in the transcription or transduction of insulin signaling pathway
summary
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