THE ENDOCRINE SYSTEM, METABOLISM

AND DISORDERS

PATHOGENESIS & DIAGNOSIS

OF DIABETES
Dr. dr. Made Ratna Saraswati, SpPD-KEMD, FINASIM

Endocrinology and Metabolism Division, Department of Internal Medicine

Faculty of Medicine, Udayana University/Sanglah Hospital, Denpasar

26th October – 30th November 2015

 References
 Gardner DG, Shoback D (editors). Greenspan's Basic &
Clinical Endocrinology. 9th edition. New York: McGrawHill,
2011.
 Harrison’s Principles of Internal Medicine 17th ed. McGraw Hill
2008. (Part 15 Endocrinology and Metabolism)
 Perkeni, 2015. Petunjuk praktis pengelolaan diabetes melitus
tipe 2. Perkumpulan Endokrinologi Indonesia. Jakarta.
 American Diabetes Association (ADA) Clinical Practice
Recommendations. Diabetes Care 2015.
 Diabetes mellitus
DM
is a syndrome of disordered metabolism with
inappropriate hyperglycemia due either to an
absolute deficiency of insulin secretion
or
a reduction in the biologic effectiveness of
insulin
(or both).

Masharani U, German MS. Pancreatic hormones and Diabetes Mellitus. In: Gardner DG, Shoback D (editors).
Greenspan's Basic & Clinical Endocrinology. 9th edition. New York: McGrawHill, 2011. p. 573-656.
 Fig. Number of people with IGT
by age (20-79 years),
2013 and 2035

IDF Diabetes Atlas 6th Edition.

Available from:
www.idf.org/diabetesatlas

Year 2013 2035

Total world population (billions) 7.2 8.7
Adult population 4.6 5.9
(20-79 years, billions)
Diabetes 8.3 10.1
Global prevalence (%)
Number of people with diabetes (millions) 382 592
IGT 6.9 8.0
Global prevalence (%)
Number of people with IGT (millions) 316 471
 WP = Western Pacific

Indonesia
an archipelago in Southeast
Prevalence Asia consisting
of diabetes of 17,000 islands
and pre-diabetes (6,000 inhabited)
in Indonesia
Adult Population (20-79) in 1000s: 154,061.95
Diabetes cases (20-79) in 1000s: 8,554.17
Diabetes national prevalence (%): 5.55
Diabetes related deaths (20-79): 172,601
IGT cases (20-79) in 1000s: 14,103.57
IGT national prevalence (%): 9.15

IDF Diabetes Atlas 6th Edition. Available from: www.idf.org/diabetesatlas

Criteria for the diagnosis of diabetes
A1C > 6.5%
The test should be performed in a laboratory using a method that is NGSP certified
and standardized to the DCCT assay.*
OR

FPG >126 mg/dL (7.0 mmol/L)

Fasting is defined as no caloric intake for at least 8 h.*
OR

2-h PG >200 mg/dL (11.1 mmol/L) during an OGTT

The test should be performed as described by the WHO, using a glucose load
containing the equivalent of 75 g anhydrous glucose dissolved in water.*
OR

In a patient with classic symptoms of hyperglycemia or hyperglycemic

crisis, a random plasma glucose >200 mg/dL (11.1 mmol/L).
*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat
testing.

American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2.

In Standards of Medical Care in Diabetesd2015. Diabetes Care 2015;38(Suppl. 1):S8–S16
 Classification
• Traditionally:
according patient’s age at onset of symptomps
juvenile-onset vs adult onset

• Based upon therapeutic classification rather than

etiologic classification
Insulin dependent diabetes mellitus (IDDM) vs
non-insulin dependent (NIDDM).

• American Diabetes Association (ADA) &

World Health Organization (WHO)
Classification
Diabetes can be classified into the following general categories:
1. Type 1 diabetes
due to b-cell destruction, usually leading to absolute insulin deficiency
2. Type 2 diabetes
due to a progressive insulin secretory defect on the background of insulin resistance
3. Gestational diabetes mellitus (GDM)
diabetes diagnosed in the second or third trimester of pregnancy that is not clearly
overt diabetes
4. Specific types of diabetes
due to other causes, e.g., monogenic diabetes syndromes such as neonatal diabetes
and maturity-onset diabetes of the young [MODY]),
diseases of the exocrine pancreas (such as cystic fibrosis),
and drug- or chemical-induced diabetes (such as in the treatment of HIV/AIDS or
after organ transplantation)

American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2.

In Standards of Medical Care in Diabetesd2015. Diabetes Care 2015;38(Suppl. 1):S8–S16
Other specific types
A. Autosomal dominant genetic defects of pancreatic βcells
1. Maturity onset diabetes of the young (MODY)
2. Insulin gene (INS)
3. ATP-sensitive potassium channel (KCNJ J J and ABBCB)

B. Other genetic defects of pancreatic 􀁵 cells

1 . Autosomal recessive genetic defects
2. Mitochrondrial DNA
3. Ketosis-prone diabetes (KPD)

C. Genetic defects in insulin action

1 . Insulin receptor mutations
2. Lipoatrophic diabetes

D. Neonatal diabetes
1 . Transient
2. Permanent
E. Diseases of the exocrine pancreas
1 . Pancreatitis 4. Cystic fibrosis
2. Trauma, pancreatectomy 5 . Hemochromatosis
3. Neoplasia 6. Fibroca lculous pancreatopathy

F. Endocrinopathies
1. Acromegaly
2. Cushing syndrome
3 . Glucagonoma
4. Pheochromocytoma
5. Hyperthyroidism
6. 5omatostatinoma
7. Aldosteronoma

G. Drug- or chemical-induced
1. β cell toxicity: vacor, pentamidine, cyclosporine
2. β cell autoimmunity: a-interferon
3 . β cell dysfu nction: thiazide and loop diuretics, diazoxide, a agonists,
β blockers, phenytoin, opiates
4. Insulin resistance: glucocorticoids, progesterone, nicotinic acid,
thyroid hormone, β blockers, atypical anti psychotic drugs,
antiretroviral protease inhi bitors
H. I nfections
Congenital rubella
2 . Other viruses: cytomegalovirus, coxsackievirus B, adenovirus, mumps

I. Uncommon forms of immune-mediated diabetes

1 . Stiff-person syndrome
2. lmmunodysreg ulation polyendocrinopathy enteropathy, X-linked
(IPEX)
3. Autoimmune polyendocrinopathy syndrome type 1
4. Anti-i nsulin receptor antibodies
5 . Ataxia telangiectasia syndrome (antireceptor antibodies)
6. POEMS syndrome

J. Other genetic syndromes sometimes associated with diabetes

1 . Chromosomal defects: Down, Klinefelter, and Turner syndromes
2. Neuromuscular syndromes: Fried reich ataxia, Hunti ngton chorea,
myotonic dystrophy, porphyria, and others
3. Obesity syndromes: Laurence-Moon-Biedl, Bardet-Biedl, Prader-Willi
syndromes, and others
4. Wolfram syndrome
Fig. Diabetes and abnormalities in glucose-stimulated insulin secretion

Harrison’s Principles of Internal Medicine, 17th ed. p. 2278

 Type 1 diabetes

• Genetic susceptibility

• Immune factors
– other autoimmune disease
– antigen-specific antibodies

• Environmental trigger
– viruses
– bovine serum albumin
– nitrosamines: cured meats
– chemicals: vacor (rat poison), streptozotin
 2. Environmental trigger
• Environmental factors that have been associated
with with altered pancreatic islet cell function
include:
– viruses (mumps, rubella, coxsackie virus B4)
– Toxic chemical agent (vacor/rat poison)
– Other destructive cytotoxin such as hydrogen cyanide
from spoiled tapioca or cassava root.
 Immune factors

Most patient with type 1 diabetes at diagnosis

have circulating antibody:
islet cell antibody (ICA)
insulin autoantibody (IAA)
antibody to glutamic acid decarboxylase (GAD) 65
antibody to tyrosine phophatases (IA-2 and IA2-β)

The most common islet cell antibodies in type 1 diabetes

are directed against GAD (glutamic acid decarboxylase),
an enzyme localized within pancreatic β cell.
Fig. Temporal model for development of type 1 diabetes

Harrison’s Principles of Internal Medicine, 17th ed. p. 2279

Fig. Relationship between genetic,
environmental, and immunological disorder
Trigger

Immunological
abnormalities
Genetic

Beta-cell
mass Clinical
diabetes

Pre-diabetes ‘Honeymoon’

Chronic
phase
Time (months - years)
Latent Autoimmune Diabetes of Adulthood

• Certain unrecognized patient with a milder

expresion of type 1 diabetes initially retain enough
B cell function to avoid ketosis but develop
increasing independency to insulin therapy later in
life as their B cell diminished
• In Europe, up to 15% of patient who supposedly
have type 2 diabetes may actually have this mild
form of type 1 diabetes (latent autoimmune
diabetes of adulthood = LADA)
Type 2 Diabetes

• 90%-95% of people with diabetes

• Insulin insensitivity and relative

insulin deficiency

• Obesity or overweight

• Complications often present at

diagnosis
 Epidemiology of type 2 diabetes

• Dramatic increase
• Aging population
• Disturbing trends parallel obesity epidemic
• Especially in adolescents and minority groups
• Increasing in young people
 Risk factors for type 2 diabetes

• Age > 40 years

• First-degree relative with diabetes
• Member of high risk population
• History of impaired glucose tolerance, impaired
fasting glucose
• Vascular disease
• History of gestational diabetes
• History of delivery of macrosomic baby
Risk factors for type 2 diabetes
• Hypertension
• Dyslipidaemia
• Abdominal obesity
• Overweight
• Polycystic ovary disease
• Acanthosis nigricans
• The genetic type of type 2 diabetes is
complex and poorly defined despite the
strong genetic predisposition in these
patients.
Insensitivity to insulin in type 2 diabetes

Glucose uptake
Glycolysis
Gluconeogenesis (amino acids)

Blood glucose

Glucose uptake
Protein degradation  amino acids

Glucose uptake
Effect of insulin resistance in type 2 diabetes

Glucose uptake
Glycolysis
Gluconeogenesis (amino acids)

Blood glucose Converted to triglycerides

Glucose uptake
Protein degradation  amino acids

Glucose uptake
 Pathogenesis of type 2 diabetes:
the triumvirate

Impaired Insulin
Secretion

Hyperglycemia

Increased HGP Decreased

glucose uptake

FIG. Insulin resistance in muscle and liver and impaired insulin secretion
represent the core defects in type 2 diabetes

De Fronzo, 2009. Diabetes, vol 58, pp. 773-95

 Pathogenesis of type 2 diabetes:
the omnious octet

Decreased Insulin Decreased Increased Lipolysis

Secretion Incretin
Effect

Increased
Glucagon Increased
Secretion Glucose
Hyperglycemia Reabsorption

Decreased
Neurotransmitter Glucose
Increased Uptake
HGP Dysfunction
De Fronzo, 2009. Diabetes, vol 58, pp. 773-95
Fig. Metabolic changes during the development of
type 2 diabetes

Harrison’s Principles of Internal Medicine, 17th ed. p. 2281

 The natural history of type 2 diabetes

Beta-cell loss
 Insulin
Primary requirements
Insulin failure with age
requirements

Endogenous
insulin

Age (years)
Fig. Insulin secretion profiles in type 2 diabetic patients
and healthy people

800
Healthy people
Insulin secretion (pmol/min)

700
Type 2 diabetic patients
600

500

400

300

200

100

6am 10am 2pm 6pm 10pm 2am 6am

Time
 Fig. Loss of early-phase insulin secretion in
type 2 diabetes

Pattern of insulin secretion is altered early in type 2 diabetes

Normal Type 2 diabetes

120 120
Plasma insulin (µU/ml)

Plasma insulin (µU/ml)

20g
20g glucose
glucose
100 100
80 80
60 60
40 40
20 20
0 0
–30 0 30 60 90 120 –30 0 30 60 90 120
Time (minutes) Time (minutes)

Ward WK, et al. Diabetes Care 1984;7:491–502.

 Glucose Homeostasis

Ingestion of
food Glucose dependent
 Insulin Insulin
from beta cells increases
(GLP-1 and GIP) peripheral
glucose
GI tract Release of Pancreas uptake
incretin gut
hormones Beta cells Blood
Alpha cells glucose control
Active
GLP-1 and GIP

DPP-4 Increased insulin

enzyme  Glucagon and decreased

glucagon
from alpha cells (GLP-1) reduce
Inactive Glucose dependent hepatic
GLP-1 GIP glucose output

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830;
Ahrén
35B Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders,
2003:1427–1483.
 Natural history of type 2 diabetes mellitus

0 4 7 10 16 20

Usual
sequence of Diet and Oral Combination Insulin
interventions exercise agents therapy with
oral agents
Risk factors for
CV disease

Typical clinical
course

IGT and Development Diagnosis Microvascular More advanced More

Death
insulin of diabetes of complications microvascular advanced
resistance diabetes and CV disease disease

CV=Cardiovascular, IGT=Impaired Glucose Tolerance

36
Adapted from Nathan DM. New Engl J Med 2002;347:1342-9