Pathogenesis of

Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus

Pugud Samodro

Department of Internal Medicine

General Soedirman School of
Medicine/ Prof Margono
Soekarjo Hospital Purwokerto
Type 2 diabetes mellitus (T2DM)

u There is an explosion of T2DM prevalence

u >370 million people with T2DM

u Need to address the pathogenesis and treatment

of this syndrome
u Macrovascular and microvascular damages of
T2DM will remain a major burden for decades to come
Global Picture 3

People living with diabetes (20-79 years) who are undiagnosed per region, 2017

IDF Diabetes Atlas 8th Edition 2017

Top 10 Countries for the Number of People with IGT (20-79 years), 2017
4

* Data was
extrapolated from
similar countries
IDF Diabetes Atlas 8th Edition 2017
Hyperglycemia in Pregnancy (20-49
years) by IDF Region, 2017 5

IDF Diabetes Atlas 8th Edition 2017

Natural history of T2DM
350 Postmeal Glucose
Prediabetes Diabetes
300
(Obesity, IFG, IGT ) diagnosis
250
200
Fasting glucose
150
100
50
-15 -10 -5 0 5 10 15 20 25 30
250 Years
200 β-cell failure Insulin resistance
150
100
50 Insulin level
0
-15 -10 -5 0 5 10 15 20 25 30
Onset Years
diabetes
Macrovascular changes

Microvascular changes
Kendall DM, et al. Am J Med 2009;122:S37-S50.
Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.
Pathogenesis of T2DM

u Multifactorial etiology & complex pathophysiology

Genetic predisposition

Environmental factors

Lifestyle choices
Epigenetics
Gene expression induced by lifestyle choices
 Genetic predisposition type 2 DM
8
CDKA1, CDKN2A, MTNR1B, TCF7L2,
CDKN2B KCNJ11 FTO IRS1, PPARG

Insulin resistance
Reduced Beta-cell
beta-cell mass dysfunction
Obesity not due to
obesity

Reduced
insulin Insulin
secretion resistance

Predisposition to
type 2 diabetes
 9

Chronological accounting of the discovery of type 2 diabetes-associated genes,

plotted by year of definitive publication and approximate effect size

Florez, J. C. J Clin Endocrinol Metab 2008;93:4633-4642

Classic view

Insulin Relative Insulin

Resistance Deficiency

Hyperglycemia
T2DM
 incretin pancreatic
Gut effect
carbohydrate insulin
delivery & secretion
peripheral absorption
glucose
uptake pancreatic
glucagon
secretion

Hyperglycemia (T2DM)

hepatic renal
glucose glucose
production excretion
Defronzo RA. Diabetes. 2009 Apr;58(4):773-95
Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Roles of β-cell loss and α-cell dysfunction

u Reduction of β-cell numbers in T2DM

u Human pancreas is incapable of renewing ↓ function
β-cells after 30yr of age
u Glucolipotoxicity and amyloid deposition
result in β-cell apoptosis through oxidative Hyper
and endoplasmic-reticulum stress stimulation

u Abnormal glucagon release by α-cells

u elevated fasting glucagon
u non-suppression after meal ingestion
cell loss

Perl S et al. J Clin Endocrinol Metab 2010; 95: E234–39

Role of Intestines
Numerous functions of GLP-1

Promotes satiety and

reduces appetite Incretins
GLP-1: Secreted upon
the ingestion of food Alpha cells:
Bile acids
Glucose-dependent
postprandial
glucagon secretion

Liver:
Glucagon reduces
Beta cells: hepatic glucose output
Enhances glucose-dependent
insulin secretion
Stomach:
Helps regulate
gastric emptying

Flint A, et al. J Clin Invest 1998;101:515-520. Larsson H, et al. Acta Physiol Scand 1997;160:413-422.
Nauck MA, et al. Diabetologia 1996;39:1546-1553. Drucker DJ. Diabetes 1998;47:159-169.
Intestinal
microbiome in
diabetes
u Gut microbiome has
>100 times genetic
information than
human genome
u Gut genome + Human
genome = Human
metagenome
Sanz Y et al. Pediatric Research (2015) 77, 236–244
Role of Kidney
Normal glucose homeostasis1,2
Net balance ~0 g/day
Glucose input ~250 g/day: Glucose uptake ~250 g/day:

• Dietary intake ~180 g/day • Brain ~125 g/day

• Glucose production ~70 g/day • Rest of the body ~125 g/day
• Gluconeogenesis
• Glycogenolysis
+ The kidney filters The kidney reabsorbs
−
circulating glucose and recirculates
glucose

Glucose filtered Glucose reabsorbed

~180 g/day ~180 g/day

1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18;

2. Gerich, JE. Diabetes Obes Metab 2000;2:345–50.
Glucose handling in Type 2 diabetes1,2

Glucose input >280 g/day: Glucose uptake >250 g/day:

• Dietary intake >180 g/day • Brain ~125 g/day

• Glucose production ~100 g/day • Rest of the body >125 g/day
• Gluconeogenesis*
• Glycogenolysis
+ Average blood glucose Increased reabsorption
−
concentration 150 mg/dL and recirculation of
Kidney filters all glucose
circulating glucose

Glucose filtered Above the renal threshold for

~270 g/day glucose (~200 mg/dL), glucose is
excreted in the urine (glucosuria)

*Elevated glucose production in patients with Type 2 diabetes attributed to

hepatic and renal gluconeogenesis.2
1. Gerich JE. Diabet Med 2010;27:136–42;
2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14:782–90.
In normal renal glucose handling, 90% of glucose is
reabsorbed by SGLT21–4
Majority of glucose
is reabsorbed by
SGLT2 (90%)

Proximal tubule

Remaining
glucose is
SGLT2
Glucose reabsorbed by
Glucose filtration SGLT1 (10%)
Minimal to
no glucose
excretion
SGLT, sodium-glucose co-transporter 2.

Adapted from: 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21;
4. Marsenic O. Am J Kidney Dis 2009;53:875–83.
Role of Brain
 Sympathetic and parasympathetic
NUTRIENTS LEPTIN nervous systems control glucose
metabolism
• directly through neuronal input
• indirectly through circulation to
affect release of insulin and
glucagon and production of
hepatic glucose.

Vagus
Hypothalamus

Steven E. Kahn, et al; Lancet. 2014 March 22; 383: 1068–1083

Role of sleep/ deprivation in diabetes

Changes in diurnal
patterns and quality of
sleep can have
important effects on
metabolic processes

Bass J et al. Science. 2010 Dec 3; 330(6009): 1349–1354.

Role of inflammation
Role of inflammation
u Obesity is characterised by u Hypothalamic inflammation might also
systemic inflammation contribute to central leptin resistance and
weight gain
u Preclinical evidence links
systemic inflammation to β-cell
dysfunction
u CRP and its upstream regulator
IL-6, are associated with insulin
sensitivity and β-cell function
u Circulating concentrations of IL
1β and IL-1 receptor antagonists
too are increased in T2DM
Luotola K et al. J Intern Med 2011; 269: 322–32.
Thaler JP et al. Endocrinology 2010;151: 4109–15.
Role of environmental factors
Role of environmental factors
↓ energy expenditure Obesity

↑ caloric intake

Body adiposity β-cell

Nutrient composition Environment dysfunction
genes
genes

? environmental chemicals

? microbiome T2DM

Steven E. Kahn, et al; Lancet. 2014 March 22; 383: 1068–1083

 Association between arsenic and diabetes in areas of high exposures

Thayer KA et al. Environ Health Perspect. 2012 Jun;120(6):779-89

Summary
Classic

Insulin Relative Insulin

Resistance Deficiency

Hyperglycemia
T2DM
 incretin pancreatic
Gut effect
carbohydrate insulin
delivery & secretion
peripheral absorption
glucose
uptake pancreatic
glucagon
secretion

Hyperglycemia (T2DM)

hepatic renal Sleep

glucose glucose Inflammation
production excretion Microbiome
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Pathogenesis Treatment
 Pathogenesis of T2DM is
not like a simple bicycle with
pedal-handle-wheels
(IR - βCF - Glucose)
It is much more complex:

Thank you
Thank you