type 2 diabetes mellitus - pathophysiology
TRANSCRIPT
Pathophysiology of Type 2 Diabetes Mellitus
Dr. Shashikiran UmakanthProfessor & HeadDepartment of Internal MedicineDr. TMA Pai Hospital - Udupi, MMMCManipal University, INDIA
Type 2 diabetes mellitus (T2DM)
There is an explosion of T2DM prevalence >370 million people with T2DM
Need to address the pathogenesis and treatment of this syndrome
else, macrovascular and microvascular damages of T2DM will remain a major burden for decades to come
Pathogenesis of T2DM
Multifactorial etiology & complex pathophysiology
Genetic predisposition
Environmental factors
Lifestyle choicesEpigeneticsGene expression induced by lifestyle choices
Microvascular changes
Macrovascular 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.
Rel
ativ
e A
mou
nt
β-cell failure
Onsetdiabetes
Glu
cose
(m
g/dL
)Diabetesdiagnosis
50100150200250300350
Fasting glucose
Prediabetes (Obesity, IFG, IGT)
Postmeal Glucose
-10 -5 0 5 10 15 20 25 30-15Years
Natural history of T2DM
Years-10 -5 0 5 10 15 20 25 30
Insulin resistance
Insulin level
0
50100
150200
250
-15
b-cell function
Incretin effect
Insulin resistance β-cell failure
T2DM
Incretin defect
Classic view
peripheralglucose uptake
hepatic glucose production
pancreatic insulinsecretion
pancreatic glucagonsecretion
Gut carbohydrate
delivery & absorption
incretineffect
Defronzo RA. Diabetes. 2009 Apr;58(4):773-95Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
renal glucose excretion
Hyperglycemia (T2DM)
Which came first?
Hyperinsulinemia
Insulin resistance
?
Pories WJ et al. Diabetes Care. 2012 Dec;35(12):2438-42
Pories WJ et al. Diabetes Care. 2012 Dec;35(12):2438-42Corkey BE. Diabetes Care. 2012 Dec;35(12):2432-37
Hyperinsulinemia
Insulin resistance
?
Steven E. Kahn, et al; Lancet. 2014 March 22; 383: 1068–1083
Feedback loop between β-cells and insulin-sensitive tissues
Roles of β-cell loss and α-cell dysfunction
Reduction of β-cell numbers in T2DM Human pancreas is incapable of renewing β-
cells after 30yr of age Glucolipotoxicity and amyloid deposition result
in β-cell apoptosis through oxidative and endoplasmic-reticulum stress
Abnormal glucagon release by α-cells elevated fasting glucagon non-suppression after meal ingestion
Perl S et al. J Clin Endocrinol Metab 2010; 95: E234–39
β ↓ function
β cell loss
Hyper-stimulation
Role of Intestines
Numerous functions of GLP-1
Stomach: Helps regulate
gastric emptying
Promotes satiety and reduces appetite
Liver: Glucagon reduces
hepatic glucose outputBeta cells:Enhances glucose-dependent
insulin secretion
Alpha cells: Glucose-dependent
postprandialglucagon secretion
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.
GLP-1: Secreted upon the ingestion of food
IncretinsBile acids
Intestinal microbiome in diabetesGut microbiome has
>100 times genetic information than human genome
Gut genome + Human genome = Human metagenome
Sanz Y et al. Pediatric Research (2015) 77, 236–244
Role of Brain
LEPTINNUTRIENTSSympathetic and parasympathetic nervous systems control glucose metabolism• directly through neuronal input• indirectly through circulation to
affect release of insulin and glucagon and production of hepatic glucose.
VagusHypothalamus
Steven E. Kahn, et al; Lancet. 2014 March 22; 383: 1068–1083
Alzheimer’s disease (AD)
Now proposed as type 3 diabetes (T3DM) Insulin resistance in brain
Brain has insulin and IGF receptors There is evidence that neurons have insulin and IGF
resistance in patients with AD
Suzanne M. de la Monte. Eur Neuropsychopharmacol. 2014 Dec;24(12):1954-60
Role of sleep/ deprivation in diabetes
Bass J et al. Science. 2010 Dec 3; 330(6009): 1349–1354.
Changes in diurnal patterns and quality of sleep can have important effects on metabolic processes
Role of inflammation
Role of inflammation Obesity is characterised by
systemic inflammation Preclinical evidence links
systemic inflammation to β-cell dysfunction
CRP and its upstream regulator IL-6, are associated with insulin sensitivity and β-cell function
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.
Hypothalamic inflammation might also contribute to central leptin resistance and weight gain
Role of environmental factors
T2DM
Role of environmental factors
Environment
Body adiposity
genes
β-cell dysfunction
genes
Obesity↓ energy expenditure
↑ caloric intake
Nutrient composition
? environmental chemicals
? microbiome
Steven E. Kahn, et al; Lancet. 2014 March 22; 383: 1068–1083
Association between maternal smoking during pregnancy and overweight/obesity in offspring
Thayer KA et al. Environ Health Perspect. 2012 Jun;120(6):779-89
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 Resistance
Relative Insulin Deficiency
HyperglycemiaT2DM
peripheralglucose uptake
hepatic glucose production
pancreatic insulinsecretion
pancreatic glucagonsecretion
Gut carbohydrate
delivery & absorption
incretineffect
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
renal glucose excretion
Hyperglycemia (T2DM)
SleepInflammationMicrobiome
Pathogenesis Treatment
Pathophysiology of T2DM is not like a simple bicycle withpedal-handle-wheels(IR - βCF - Glucose)
It is much more complex:
Thank you
Thank you
Questions
Question 1
Which factors determine development of insulin resistance and β-cell dysfunction?
A. Genes, environment and lifestyle together are important determinants
B. Genetic factors aloneC. Obesity alone, by triggering hyperstimulation of β-cells
causing their failureD. None of the above
Question 2
Example of environmental factors that influence development of T2DM include
A. Saturated fats in dietB. Arsenic exposureC. Gut microbiomeD. All of the above