Diabetes mellitus and insulin

resistance

A/prof. Barbara Ukropcova, MD, PhD

Institute of Pathological Physiology, Faculty of Medicine, CU

Biomedical Research Center, Slovak Academy of Sciences

04-2020

• Epidemiology

• Summary of physiology of metabolic regulation by insulin

• Characteristics & klasification of diabetes mellitus

• Pathophysiology of diabetes mellitus; insulin

resistance

• Signs and symptoms

• Type 1 diabetes

• Type 2 diabetes

• Complications

• Therapy

• Metabolic syndrome

Prevalence of type 2 diabetes and prediabetes(preclinical stage of T2D; IGT, Impaired glucose tolerance)

DeFronzo, R. A. et al. 2015

Type 2 diabetes, associated with obesity and sedentary lifestyle,

is the most common type of diabetes, representing >90% of all diabetics

Global prevalence: Prediabetes

According to IDF, global prevalence of prediabetes is ~352 million (2017). According to

predictions, this number will increase up to 500 million (2045), and number of patients with

T2D will be surpass 400 million. (Hostalek 2019)

Del Prato http://www.medscape.org/viewarticle/412864

The prevalence of disorders of glucose metabolism increases with age

• Global prevalence of type 2 diabetes is 9,2%

• Diabetes mellitus is 4th leading cause of death

Diabetes mellitus

Glucose homeostasis

• Insulin

Glucose-lowering

effect

• glucagon

• catecholamines

• cortisol

• growth hormoneCounter-regulatory

hormones, increase blood

glucose levels1.Fasting conditions:

glucose production (from lactate, aminoacids, glycerol)

in liver and kidney (gluconeogenesis)

2. Postprandial period (after meal):

glucose from ingested meal;

suppresion of glucose production by insulin

Langerhans’s islets: The endocrine archipelago in an exocrine gland

• Discovered by Paul Langerhans in 1869

• One islet measures 0,5 mm

• ~ 1 million islets, total weight 1 gram

• Islets represent ~ 2 % of pancreas

Changes of Langerhans’s islets in

diabetes

Healthy individual Atrophy in diabetes

B cellsA cells

In diabetes, there are

changes in the islets, with

the destruction of B-cells,

fibrosis and accumulation of

amyloid (in T2D), which

results in the islets’ atrophy.

Cells of Langerhans’s islets

• A cells, glucagon (20 %)

• B cells, insulin (68 %)

• D cells, somatostatin (10 %)

• PP cells, pancreatic polypeptide (2 %)

Human insulin

- Discovered by: dr.

Banting and medical

student Best

(Nobel price in 1923:

Banting & Mcleod)

- Administered for the

first time to a 14-year

old boy in diabetic

ketoacidosis, in Toronto

Preproinsulin

Insulin

Proinsulin

mRNA

DNA

C-peptide

(connecting peptide),

orange:

Secreted from B-cells

in amounts equimolar to insulin,

a marker of endogenous

Secretory capacity

of B-cells

Organ-specific effects of insulin

Liver

• stimulates glycolysis and glycogen synthesis• stimulates uptake of chylomicrones

and production of VLDL• stimulates synthesis of TAGs (triacylglycerols)

• inhibitsgluconeogenesis andglycogenolysis

Muscle

• stimulates glucose uptake(transporters GLUT-4) andglycogen synthesis

• stimulates aminoacids uptake andproteosynthesis

• inhibits glycogenolysis

Adipose tissue

• stimulates glucose transport (transporters GLUT-4) • increases activity of lipoprotein lipase,

which hydrolyzes circulating lipids

• inhibits intracellularTAGs breakdown

• Antilypolitic effect

(adipose tissue)

• Suppression of glucose production

(liver)

• Uptake of glucose

(skeletal muscle, adipose tissue)

Major effects of insulin at a tissue level

Insulin effects at a molecullar level

Apart from metabolic

effects, insulin also

exerts

mitogenic effects

(it stimulates

cellular proliferation).

This effect can promote

carcinogenesis under

conditions

of chronic

hyperinsulinemia,

associated with obesity

and insulin resistance.

Insu

lin

secre

tio

n

High blood glucose

time0 5 min

baseline

2. phase

1. phase

Dynamics of stimulated insulin secretion

Insulin secretion has two

components:

Baseline insulin secretion

(during 24 hours, independent

from food intake)

Stimulated insulin secretion

(secretion of insulin after the

meal)

First phase of glucose-

stimulated insulin secretion

lasts for 10 minutes, includes

exocytosis of secretory

granules in the close vicinity of

plasma membrane.

Second phase: synthesis of

new molecules of insulin, and

secretion of granules that are

not in the membrane vicinity.

Pickup and Williams, 2003

What is diabetes mellitus?1. Diabetes mellitus is a syndrom with insulin deficit

• absolute; type 1 diabetes / T1D

• relative (defect of insulin effect); type 2 diabetes / T2D

2. Major characteristics

• a complex disorder of metabolism (lipids, sacharides, proteins)

• chronic hyperglycemia (decreased glucose uptake by skeletal

muscle, excessive glucose production in liver)

3. Typical signs and symptoms

polyuria, polydipsia, pruritus, loss of weight and/or

complications

4. T2D can be asymptomatic; diagnosis based on biochemical parameters

5. Disorder of glucose homeostasis can be present transiently

disorder of glucose metabolism in pregnancy (gestational diabetes

mellitus)

Fasting glycemia

2-hours glycemia

NORMAL

< 7,8 mmol/l

PREDIABETES

7,8 - 11,0 mmol/l

DIABETES

> 11,0 mmol/l

NORMAL

< 5,6 mmol/l

PREDIABETES

5,6 - 6,9 mmol/l

DIABETES

> 6,9 mmol/l

Prediabetes – preclinical stage of type 2 diabetes:IGT: Impaired Glucose Tolerance

IFG: Impaired Fasting Glucose

American Diabetes Association / ADA criteria

• High risk of the development of type 2 diabetes

• IGT

• IFG

Pathogenesis of DM symptoms

Insulin hyperglycemia → glycosuria (glucose

is osmotically active) → polyuria → dehydration

→ polydipsia

Tissue starvation → loss of muscle and lipid

tissue + loss of minerals and water → weight

loss despite increased food intake → cachexia

Excessive mobilisation of lipids (lipolysis) from the

adipose tissue → hyperlipidemia → increased oxidation

of FFA → high levels of acetylCoA, used for the ketones

synthesis in the liver → hyperketonemia → metabolic

acidosis, ketonuria

Acute signs

and symptoms

of DM

kidney

glycosuria

aminoaciduria

polyuria

loss of electrolytes

dehydration

coma

acidosis

foetor

Kussmaul’s

breathing

aldosteron

ketone

bodies

osmolarity

fatty acids

lipolysisproteolysis

aminoacids

muscle

weakness

weight

loss

hyperglycemia

thirst

insulin deficit

glucose

production

glycogenolysis

liver

steatosis

decreased

glycolysis

in the cell

decreased glucose

uptake by skeletal muscle

& adipose tissue due to the

lack of insulin

Signs & symptoms

• Type 1 diabetes mellitus / T1D

• Type 2 diabetes / T2D

• Other specific types of diabetesgenetic defects of insulin secretion and action

diseases of exocrinne pancreas

diabetes induced by drugs – AIDS therapy, immunossupression after the organ transplantation

• Gestational diabetes mellitusdiagnosed during pregnancy (2nd or 3rd trimester)

6 months after the delivery - reclassification

Classification of diabetes mellitus

I. Type 1 diabetesA. Autoimmune (over 90% of T1D cases)B. Idiopathic

I. Type 2 diabetes

I. Other specific types of diabetesA. Genetic defects of B cells1. Chromosom 12, HNF-1 (MODY3)2. Chromosom 7, glukokinase (MODY2)3. Chromosom 20, HNF-4 (MODY1)4. Mitochondrial DNA5. otherB. Genetic defects of insulin action

1. Type A insuline resistance2. Leprechaunism3. Rabson-Mendehall’s syndrom4. Lipoatrophic diabetes5. Other

Ethiopathogenetic classification of diabetes

C. Diseases of exocrinne pancreas

1. Pancreatitis

2. Trauma/pancreatectomy

3. Tumors

4. Cystic fibrosis

5. Hemochromatosis

6. Fibrocalculos pancreopathy

7. Other

D. Endocrinopathies

1. Acromegaly 5. Hyperthyroidism

2. Cushing’s syndrom 6. Somatostatinoma

3. Glucagonoma 7. Aldosteronoma

4. Feochromocytoma 8. Other

E. Drugs and chemicals

1. Vacor 7. ß-adrenergic antagonists

2. Pentamidine 8. Thiazides

3. Nicotinic acid 9. Dilantine

4. Glucocorticoids 10. Α-interpheron

5. Thyroid hormones 11. Other

6. Diazoxide

F. Infections1. Congenital rubeola

2. Cytomegalovirus

3. Other

G. Less common forms of immune-based diabetes1. „Stiff-man“ syndrom

2. Antibodies against insulin receptors

3. Other

H. Other genetic syndroms sometimes associated with

diabetes

1. Down’s syndrom 7. Lauren-Moon-Biedel’s sy

. 2. Klinefelter’s sy 8. Myotonic dystrophy

3. Turner’s syndrom 9. Porphyria

4. Wolframov syndróm 10. Prader-Willi’s syndrom

5. Friedreichova ataxia 11. Iné

6. Huntingtonova chorea

IV. Gestational diabetes mellitus

• glycemia ≥11.1 mmol/l, with symptoms of diabetes

• FPG ≥7 mmol/l (after minimum 8h fasting)

• 2-hour glycemia in oGTT ≥11.1 mmol/l

PrediabetesIFG - Impaired Fasting Glucose 5.6 – 6.9 mmol/l

IGT - Impaired Glucose Tolerance 7.8 – 11.0 mmol/l

(after 2 hours of oGTT)

Diagnostic criteria for diabetes mellitus according to American Diabetes Association, ADA

Diagnostic criteria for diabetes mellitus according to ADA

Glycated hemoglobin (HbA1c) ≥6.5 mmol / l

Type 2 diabetes

• diagnosis depends on the confirmation of hyperglycemia

• initial test: fasting glucose in blood or plasma

• if fasting glycemia is lower → oral glucosetolerance test (oGTT) can be indicated, which confirms or excludes T2D or IGT

Diagnosis of type 2 diabetes

• based on the confirmation of hyperglycemia

• the initial test: fasting glycemia (or HbA1c)

• in pregnancy: oGTT (oral glucose tolerance test)

oGTT – 2 hour glycemia

1. Normal glucose tolerance – NGT:

less than 7.8 mmol / l

1. Impaired glucose tolerance - IGT:

7.8 – 11.0 mmol / l

1. Type 2 Diabetes mellitus

≥11.1 mmol / l

Diagnosis of diabetes mellitus

• Signs and symptoms of complications –

target organs

• Parameters of metabolic syndrome

• Family history of diabetes

Therapy:

• Lifestyle modification / intervention, weight loss

• Pharmacotherapy

• Metabolic surgery (reversal of diabetes in early

stages, obesity management)

Type 1 diabetes

• destruction of B cells, insulin, absolute insulin

deficit(to a smaller extent, defects in insulin action)

• hyperglycemia and its symptoms: polydypsia,

polyuria, hunger, polyphagia, weight loss

• deteriorated regulation of lipolysis( keton bodies → ketosis and ketonuria → metabolic acidosis, coma, exitus)

• insulinotherapy: inevitable to achieve the control of

glycemia and as a prevention of ketoacidosis

Type 1 diabetes

• the most common type of diabetes in children

and adolescents (though the proportion of T2D in this age

category increases, due to increasing incidence of obesity)

incidence in North Europeans

• incidence with age till adolescence & then

• it affects people of all age groups

• it represents around 10 % of all types of DM

Ethiological classification of T1D

A. Autoimmune destruction of B cells

B. Typ II polyglandular autoimmune syndroms Schmidt’s sy

C. Viral infection with destruction of B cellscongenital rubella, coxsackie virus B, cytomegalovirus

A. Loss of pancreatic tissueacute and chronic recurrent pancreatitis, carcinoma, congenital hypoplasia, pancreatectomy

A. Chemical compounds affecting pancreasN-3 pyridymethyl-N-p-nitrophenylurea

A. Genetic syndromsDIDMOAD sy*, Friedreich’s ataxia

A. Idiopathic__________________________________________*diabetes insipidus, diabetes mellitus, atrophy of nervus opticus, deafness

Type 1 diabetes

• autoimmune destruction of B cells

evidence: antibodies against cells of islets (ICA)

antibodies against insulin (IAA)

antibodies against decarboxylase of

glutamate (GAD)

• autoimmune destruction of B cells is most common in

patients with certain HLA types ( DR4, DQw8)

• initiation of autoimmune reaction: triggered by viruses?

chemicals?

• other causes of type 1 diabetes are less common

Gillespie, K. M. CMAJ 2006;175:165-170

Presentation of antigen(peptides of proinsulin) to CD4 T lymphocytes

via HLA II molecules on antigen presenting cell

Antibodies in type 1 diabetes

Environmental influences on the T1D

• viral infections

• other factors:

• lower risk of T1D in brestfed children

(bovine albumin from cow milk more antigenic)

• risk of T1D correlates with average year temperature and

the distance from the equator

(more T1 diabetics have light skin and eyes and higher

sensitivity to UV radiation)

Autoantibodies and prediction of T1D

• high ICA signals the risk of type 1 diabetes in

patient’s relatives (8-10 % will be type 1 diabetics)

• combination of high ICA and IAA constitute even

higher risk

• ADA recommends screening of autoantibodies in

first degree relatives as a prevention of diabetes

Gillespie, K. M. CMAJ 2006;175:165-170

Potential targets of therapeutic intervention in type 1 diabetes

PREVENTION

Identification and

abolishment of the

environmental factor

REVERSAL OF DISEASE

PROGRESSION

Islet transplantation

Gen therapy

• anti-T lymfocyte

strategies

• induction of tolerance

• regulation of T-lymfocytes

• Regeneration

of B cells

• Resources of

islets

Diagnosis of type 1 diabetes (less

than 20% islets)

Antibodies against

islets

Genetic predisposition

Environmental

influences

Immunosupression in therapy of T1D

Hypothesis

Immunosupression will prevent progressive

deterioration of B cell function

• cyklosporin A:

plus: remission of diabetes up to 2 years

minuses: acute and chronic nephrotoxicity

• azathioprine with prednisone: 1 year remission

• nicotinamide: remission 1-2 years

Future: safe immunosupression before clinical

manifestation of T1D in individuals with positive

autoantibodies

Immunomodulation in therapy of T1D

• Monoclonal anti-CD3 antibodies: induction of

immune regulation by monoclonal antibodies

• Effective in maintaining insulin secretion during first

two years of disease

• the aim: to keep and improve the function / quantity

of B cells

Summary T1D

• absolute insulin deficit

• autoimmune disease

• genetic predisposition + environmental factors

• preclinical phase (autoantibodies)

• clinical manifestation of type 1 diabetes is associated

with the death of majority of B cells (over 80%)

Summary II

Viral infection Autoimmune disease

B cells (pancreas)

Type I

10%

diabetics

Absolute insulin

deficit

Lipolysis Hyperglycemia Proteolysis

Destruction of B cells

Genetic

predisposition

Type 2 diabetes

• defects of insulin action, dysfunction of B cells

• T2D represents ~90 % of all diabetics

• obesity increases the risk of T2D 4x

• long asymptomatic period

• positive family history of diabetes

• up to 90% T2D are obese

• heterogenous syndrom → pathogenesis is not clear

The link between BMI, age and type 2 diabetes

DeFronzo, R. A. et al. (2015) Type 2 diabetes mellitus

Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.19

T2D and BMI T2D and age

IDF Global Fact sheets, 2019

Type 2 diabetes

• manifestation: 1. classical signs & symptoms

2. complications

3. asymptomatic

• ketoacidosis is very rare (usually linked to stress, such

as serious infection, surgery, trauma… )

• the risk of hyperosmolar hyperglycemic coma

• insulin is not necessary (to prevent ketoacidosis…)

• insulin might be important for the control of

glycemia

Type 2 diabetes • Insuline resistance

skeletal muscle: lower glucose uptake, lower oxidative and nonoxidativeglucose utilisation

adipose tissue: lower antilipolytic effect of insulin (increase in FFA)

lower uptake of glucose

liver: lower suppression gluconeogenesis = higher endogenous glucose production

Metabolic inflexibility

skeletal muscle: lower ability to switch fat oxidation to glucose oxidation during insulin stimulation

- uptake of glucose stimulated by insulin is 60 % lower!

- 80% more fats in insulin resistant celle

• Defects of secretory capacity of B cells

Insulin resistance

Obesity, T2D, systemic diseases COPD, tumors, cachexia, connective tissue diseases, sepsis, cardiac

insufficiency, cirrhosis…

also in otherwise healthy individuals immobilisation, high fat diet, stress (trauma, injury, infection…), pregnancy, aging…

Prereceptor

• immunity, metabolism, genetics

• in the past: antibodies against exogenous insulin

Receptor

• a decrease in tyrosinkinase activity, increased degradation…

• rarely – mutation of the receptor genes...

Postreceptor (the most common cause, induced by chronic low-gradeinflammation and lipotoxicity)

• Signaling pathways, glucose transport, enzymes of glycolysis,protein synthesis

Effects of 2 weeks of physical inactivity on insulin

sensitivity in young lean healthy adults

Krogh-Madsen R et al. J Appl Physiol 2010;108:1034-1040

• reduced VO2max (aerobic

physical fitness) by 7%

• reduced muscle mass and

strength

• increased visceral fat

by 7%

Two weeks of inactivity

can reduce your insulin

sensitivity by 20%

Knudsen S H et al. J Appl Physiol 2012;113:7-15

Effects of 2 weeks of physical inactivity AND

overeating in healthy young individuals on:insuline sensitivity visceral adipose tissue

Two weeks of physical inactivity and overeating can increase your

visceral fat by ~30% and reduce your insulin sensitivity by 30-40% (!!)

Progression of B-cell dysfunction in the

development of T2D

Prentki a Nolan, 2006

The association between B-cell mass and their

function

DeFronzo, R. A. et al. (2015) Type 2 diabetes mellitus

Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.19

The ominous octet: 8 principial components of

T2D pathomechanisms

DeFronzo, Diabetes 2009; DeFronzo et al, review 2018

Principal pathomechanisms in T2D:

complex pathogenesis of type 2 diabetes

DeFronzo, Diabetes 2009; DeFronzo et al, review 2018

• 2x pancreas (reduced insulin secretion, increased secretion of glucagon)

• GIT (dysregulation of incretins, hormones from the small intestine, which

potentiate glucose-induced insulin secretion; changes in microbiome)

• adipose tissue (dysregulation / increased lipolysis)

• kidneys (increased reabsorption of glucose)

• skeletal muscle (reduced glucose uptake)

• liver (increased gluconeogenesis)

• brain (dysfunction of neurotransmiters)

Pathophysiology of T2D: the implications for therapy

DeFronzo et al, 2015

GIT:

The effect of thiazolidindions

Redistribution of adipose tissue: reduction of visceral /

ectopic fat, an increased differentiation capacity of

subcutaneous fat to store lipids – metabolic health

DeFronzo review 2009

type 2

diabetes

Genes„Thrifty“ genotype–

Energy storage

EpigeneticsEnvironmental imprinting of the genome,

which influences the gene expression patters,

and which is transferable between cellular

populations and/or from parents to offspring; it

is also a tool of early reprogramming, with an

impact on the risk of diseases in the adulthood

(in utero, early childhood)

Lifestyle(caloric excess,

Reduced physical

activity)

Interaction of genes with the environment

Pima Indians Arizona

1885 present

http://optimalhealthsource.blogspot.sk/2011/04/are-genes-responsible-for-modern.html

http://www.earlypics.com/2012/05/pimo-indians-arizona-elias-bonine-1875.html

Genetic predisposition

for diabetes in Pima

Indians

is translated into diabetic

phenotype when

confronted with obesity /

caloric excess / sedentary

lifestyle

Types of obesityAndroid / abdominal & gynoid / gluteofemoral

• intraabdominal

adipose tissue

• high risk of

T2D and CVD

• subcutaneous

adipose tissue

• low risk of

T2D and CVD

Nature. 2008 July 24; 454(7203): 463–469.

„Gluttony and Sloth“(Unger, Scherer, 2010)

65% global mortalityBlair SN, Archer E et al, 2012

Visceral obesity

Dysfunctional adipose tissue

Lipotoxicity

Chronic systemic inflammation

Insulin resistance

Metabolic

syndrome

Despres, Lumieaux, Nature 2006

Adipose tissue

• subcutaneous

• visceral

(intraabdominal)

Adapted from Després JP a Lemieux I, 2006.

Positive Energy

Balance

Normal adiposity

Subcutaneous obesity

“Healthy” adipose tissue

Visceral obesity

Adipose tissue dysfunction

Normal metabolic

profile

Altered metabolic

profile

Where is the fat stored? …lipid spill-over into other organs, after surpassing the

capacity of the subcutaneous adipose tissue to store

excessive calories as lipids (TG, triglycerides)

Unger RH, et al., Lipid homeostasis, lipotoxicity and the metabolic syndrome Biochim Biophys Acta. 2010; 1801:209-14

*Foster DJ, et al., Fatty diabetic lung: altered alveolar structure and surfactant protein expression. Am J Physiol. 2010; 298:L392-403

Lipotoxicity: storage of lipids in the form of ectopic

adipose tissue (in the organs)

Lipotoxicity: mediated by intermediate metabolites of

lipid metabolism, such as (diacylglycerols, long-chain Acyl-CoAs,

ceramides...); it contributes to the chronic systemic low grade

inflammation, insulin resistance, mitochondrial dysfunction

Schenk S, et al., Journal of Clinical Investigation. 2008

LPC, AA

Dysfunctional, „pathogenic“ adipose tissue

inflammatory infiltration of the adipose tissue

Hypertrophic

Hyperplastic

Big adipocytes: insulin-resistant, inflammation in the adipose tissue, which contributes

to the systemic inflammation

Small adipocytes: insulin-sensitive, absence of inflammation in the adipose tissue,

better differentiation capacity and the capacity to store lipids

No inflammation

Metabolic

health

Inflammation

Metabolic

disease

Kadowaki et al., 2006

The insulin resistant phenotype of liver & skeletal

muscle is associated with adipose tissue qualities

obese adipose tissue

lean adipose tissue

Glucose utilization

Glucose production

CRP, SAA,

Insulin secretion

Beta cell

TYPE 2 DM

FFA TNF-a, resistin

IL-6, IL-18, PAI-1

adiponectin

Mechanisms of insulin resistance

DeFronzo, R. A. et al. (2015) Type 2 diabetes mellitus

Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.19

- Change in the secretory

profile of the hypertrophic

adipocyte

- Activation of

inflammatory

pathways (TLR4, TNFR)

- Lipotoxicity

- Oxidative stress

(accumulation of ROS)

- ER stress

- Postreceptor

insulin resistance

Insulin

Glucose

Dyslipidemia

Inflammation

Hypertension

Smoking

Obesity

Physical inactivity

Sleep disorders

Stress

...

Type 2. diabetes

Cardiovascular disease

Oncologic disease

Neurodegenerative disease...

brain, liver, B cells

Skeletal muscle...

Genetic predisposition

Environmental factors

insulin secretion insulin resistance

liver glucose production

transport of glucose to tissues

antilipolytic effect

HYPERGLYCEMIA

FREE FATTY ACIDS

glucotoxicity, lipotoxicity

defects of

B cells

basal

hyperinsulinism

“down”-regulation of

insuline receptors

defects of skeletal

muscle

Summary – T2D

Genetic

predisposition

Insulin resistance

Type II

~90%

diabetics

Insulin

Lipolysis

Energy intake /

energy expenditure

Obesity

Target

cell

Ketone bodies

Free fatty acids

Relative insulin

deficit

Hyperglycemia

Summary: comparison of T1D & T2D

Genetic

predisposition

Insulin resistance

Type II

~ 90%

diabetics

Insulin

Lipolysis

Energy intake /

energy expenditure

ObesityTarget

cell

Ketone bodies

Free fatty acids

Relative insulin

deficit

Hyperglycemia

Viral infection Autoimmune disease

B cells (pancreas)

Type I

~10%

diabetics

Absolute insulin

deficit

Lipolysis Hyperglycemia Proteolysis

Destruction of B cells

Genetic

predisposition

Type 1 DM - typically

young, lean individuals

Type 2 DM - typically

older, obese individuals

When is your patient

at a higher risk of

developing T2D

InsulinResistance

(common denominator)

Prediabetes,

IR

Visceral

obesity

Dyslipidemia(higher TAG, lower

HDL-chol)Hypertension

Metabolic syndrome: ≥3 out of 5 parameter(in red rectangles, changes in lipid profile represent two independent

parameters)

Low physical

fitness (not

officialy)

Low adiponectineInflammation

HyperuricemiaNAFLD / Steatosis

Metabolic sy increases the risk

of cardiometabolic, but also neurodegenerative and specific oncologic diseases.

MSy is present in ~30% of adult population (higher in older age groups)

Complications of diabetes

1. Acute• Hyperglycemic coma

– with ketoacidosis (T1D)

– without ketoacidosis (T2D)

• Hypoglycemic coma (insulin or PAD, intensive physical

activity...)

2. Chronic• Microangiopathy, macroangiopathy

• Neuropathy, nephropathy

• Infections, gingivitis, cataract...

• Impaired immune functions

• Impaired wound healing

Del Prato http://www.medscape.org/viewarticle/418580_2

Sustained elevated

blood glucose

levels, or even

glucose levels that

wax and wane,

cause toxic effects

to tissues.

Controlling both

postprandial and

fasting blood

glucose levels is

essential for

efficient prevention

of chronic

complications.

Chronic complications of diabetes

retinopathy nephropathy neuropathy

https://en.wikipedia.org/wiki/Diabetes#/media/File:Diabetes_complications.jpg

Diabetic complications – target organsDiabetes mellitus is the most common cause of

blindness, kidney failure, lower limb amputation

Diabetic foot

Combination of diabetic

• microangiopathy

• macroangiopathy (ischemia of tissues)

• neuropathy (reduced sensory perception…)

&

• impaired immune functions, edema of tissue

(impaired wound healing)

Pathogenesis of complications

Ketones

Sorbitol

Advanced Glycation End products (AGEs)

Reactive Oxygen Species (ROS)

Pathogenesis of diabetes complicationsSorbitol (activation of polyol pathway in non-insulin dependent tissues with high

activity of aldosoreduktase; pericytes of capillaries, lens, neurons), pseudohypoxia

Advanced Glycation End products (AGEs)

(non-enzymatic glycation of proteins; plasma, cells, tissues; accumulation in the artery wall, in mesangium of glomerulus, in basal membranes...); it exerts effect upon functional qualities of proteins

Reactive oxygen species (ROS), (mitochondria, chronic hyperglycemia,...); damage of cell membranes by lipoperoxidation; activation of NFkB signaling

Activation of proteinkinase C (proliferation and fibrotisation, inflammation, oxidative stress)

Hexosamine pathway (sensor of energy sufficiency, glucosamine-6-phosphate, insulin resistance in adipose tissue and skeletal muscle)

MicroangiopathyComplex functional and structural changes

Capillary wall Extravascular tissue

Early changes

• Endothelial dysfunction(increased permeability, adhesion, production of inflamm. cytokines, growth factors....)

• Apoptosis of pericytes

Early functional changes

• activation of mesangial cells and fibroblasts (rastové faktory, väzivo)

• activation of macrophages(zápalové cytokíny)

Late changes

• Angiogenesis (proliferation of

capillaries, neovascularisation)

Late structural changes

• thickening of basalmembranes

• fibrous tissue proliferation

Del Prato

Postprandial elevation of

glucose may exert both

short-term and long-term

effects on the vasculature.

The hyperglycemic wave can

trigger events ultimately

contributing to vessel wall

oxidative stress and

atherosclerosis. Tight control

of hyperglycemia can

minimize these vascular

effects and reduce the risk of

cardiovascular complications

in patients with diabetes.

The aim of therapy

• Metabolic

compensation of

diabetes

• Lifestyle modification

• peroral antidiabetics

metformin, sulfonylurea

incretin analogs, DPP4

inhibitors...

• Insulin (when endogenous

secretory capacity is substantially

reduced)

• Chronic complications

Control of other risk

factors:

• Hypertension

• Dyslipidemia

• Smoking

• Management of chronic

inflammation

• Dental hygiene

• …

„Walking is the best medicine.“

„Sport is the health protector.“

Hippocrates

Prescription of exercise as an essential component of

complex lifestyle modification in the prevention and treatment

of type 2 diabetes:

Evidence based medicine

Diabetes Prevention Program, USA

(Knowler et al, NEJM 2002)

Finish Diabetes Prevention Study

(Tuomilehto et al, NEJM 2001)

Da Qing Study (Pan et al, Diabetes

Care,1997)

Indian Diabetes Prevention Program

(Ramachandran et al, 2006)

Prevention of T2D by lifestyle, Japan

(Kosaka, 2005)

Intervention studies in prediabetics, aimed at the

prevention of type 2 diabetes

DPP Research Group, 2015 Lancet

Cum

ula

tive

incid

ence

of ty

pe 2

dia

bete

s

Li et al, 2008 Lancet

58%

31%

0

20

40

60

80

100

Ris

kre

du

ctio

n(%

)

- exercise with medium

intensity 150 min/week - low caloric, low fat diet - education

Lifestyle Intervention

Metformin

>3200 patients with prediabetes, ~2,8 year follow-up

Clinical studies with the complex lifestyle

modification document efficiency and

long-term sustainability of lifestyle

interventions

PREVIEW: PREVention throught lifestyle intervention…

• Multinational study to prevent type 2 diabetes in prediabetic individuals with

BMI >25kg/m2, all age groups

• Fixed LED for 8 weeks (Cambridge Weight Plan), the aim: weight loss of at

least 8%

• n=2224 at baseline, 2020 after 8 weeks (>90%)

• Average weight loss after 8 weeks: ~11%

• 35% of patients reverted into normoglycemia after 8 weeks

• 3-year follow-up, weight maintenance (diet + physical activity + CBT)

• 96% did not progress into T2D during 3-y FU (DPP – 91%)

• weight loss of 10% was sustained in those who remained in the study (43%

vs. 92% in DPS)

EASD Berlin 2018

Christensen, Raben et al, DOM 2018

Swindell, Stratton et al, Diabetes Care 2018

Intervention study DiRECT: weight loss with the aim to induce

remission of T2D, coaching by the general practitioners

• intensive weight management

within routine primary care to

achieve remission of T2D

• 306 individuals from 49

(intervention and control)

general practices;

• patients with T2D, 20-65 years,

BMI 27-45 kg/m2, w/o insulin.

• at 12 months, weight loss of 15

kg or more in 36 (24%)

participants in the intervention

group and no participants in

the control group (p<0·0001).

• Diabetes remission in 68 (46%)

participants in the intervention

group and six (4%) participants

in the control group (at 12-

month).

Wweight loss at 12 months [kg]

PrescriptionPatient‘sID

number

Nameandsurname

Residence

Dateofbirth

Code

AA0972203HealthInsuranceGroup

Rp.

Dg.

ü 10 000 steps daily

ü 30 minutes moderate-intensity physical activity

5 times weekly

ü 60 minutes high-intensity physical activity

3 times weekly

ü 60 minutes of strength exercise 2 times weekly

acceptedby preparedby date

………………………………………………….Stampandsignature

Code

• 8 000 steps / day

• ≥ 30min medium intensity

aerobic activity, ≥ 5 days / week

• 2-3x / week strength exercise

• Interruptions of sedentary

behavior

• psychiatric diseases (depression, anxiety, stress,

schizophrenia);

• neurological diseases (dementia, Parkinson's

disease, multiple sclerosis);

• metabolic diseases (obesity, hyperlipidemia, MS,

PCOS, T2D, T1D);

• CVD (hypertension, coronary heart disease, heart

failure, cerebral apoplexy, claudication intermittent);

• pulmonary diseases (COPD, asthma, cystic

fibrosis);

• musculo-skeletal disorders (osteoarthritis,

osteoporosis, back pain, rheumatoid arthritis);

• cancer

Exercise prescription in clinical practice

Learn more about diabetes and obesity

www.diabetes.org/home.jsp

www.idf.org

www.iaso.org/

Thank you for your time.

If you have any questions on the topic:barbara.ukropcova@gmail.com