Metabolic pathologies Diabetes & Obesity

induced by infection, tissue injury & tissue stress, and malfunction

physiological purpose: host defense against infection, tissue repair response & adaption to stress & restoration of a homeostatic state

small proteins normally helping to stimulate & regulate the immune system & control inflammation (interleukins, chemokines, TNF, interferon=

coordinate by recruiting specific cells or by inhibiting their functions by regulating cell proliferation & differentiation, by activating or inhibiting the expression of certain genes

dual-edged sword: required for proper immune system function but in mild to moderate excess they can cause or exacerbate disease

1. acute inflammation

2. resolution

3. postresolution

pro-inflammatory: from M1-macrophages secreting TNFα, IL-1—>matrix degradation, tissue destruction

anti-inflammatory: from M2-macrophages secreting IL-10 —> angiogenesis, matrix synthesis, tissue remodeling (reparation afterward)

suppressor of cytokine signaling after activation of a receptor

cytokine receptor family: interleukin type I & II, TNFR, Ig family

activation of JAK/STAT, PI3K/AKT, MAPK and NFκB pathways activated

found in almost all animal cells

stimuli: stress, cytokines, free radicals, heavy metals, UV, oxidized LDL, and bacterial or viral antigens

gene induction: anti-apoptotic factors, cell cycle regulators, cytokines, chemokines, adhesion molecules

if no counter-part / anti-inflammatory cytokines

autoimmunity, inflammatory tissue damage & sepsis

fibrosis, metaplasia and/or tumor growth

shift in homeostatic set points, development of diseases of homeostasis and/or autoinflammatory diseases

old disease (<2000 before Christ in papyrus)

17th century: glucose in urine (sweet)

1909: insulin = hypoglycemic substance form the pancreas

1922: first injection of insulin in human

chronic hyperglycemia

fasting glycemia: glucose > 7mM in diabetes

post-prandial glycemia: glucose > 11.7 mM

give 75 g of glucose & measure glycemia 2h after oral ingestion

if intolerant disturbed answer—>glycemia increases higher than normal (above 11 mM), can reach a normal low level in a pre-diabetic state

normal: increase for 1h, after 2 h back to normal

nonenzymatic glycation of hemoglobin

reflect glycemia stability during the past 2 months

4-6% normal

deactivation of some proteins

insulin < 5uU/mL—>hypoinsulinemia (pancreas affected)

insulin > 20 uU/mL —>hyperinsulinemia (insulin resistance)

in nephron (functional unit) of the glomerulus—>exchange blood

loop of Henle with a capillary network: collective tubes produce urine

proximal tubule: exchange with blood —>reabsoprtion of molecules

99% of the filtrate is reabsorbed by active or passive transport

1% (1-1.5L) in urine

normally no glucose & proteins in urine & excretion of urea

mainly in the proximal convoluted tube

consequence of Na+ reabsorption by active transport in the PCT (SGLT)

Na+ reabsorption induces hypertonicity —>water follows by osmosis

—>water follows sodium and glucose is co-transported

SGLT1&2: secondary active transport of glucose (Na+/K+ pump leads to indirect consumption of energy)

limited quantity of a substance that can be transported within a certain time due to a limited number of transporters

if glycemia is higher than 11.1 mM, Tm is exceeded and glucose that has not been reabsorbed is then found in urine —>glucosuria

prediction of increasing incidence in South America, Africa & Asia

high number of co-morbidities (cardio-vascular complications, acute metabolic, macrovascular / microvascular, neuropathies)

high cost: due to chronicity —>treatment throughout the life

in developed countries first cause of blindness in adult, kidney failure & atraumatic lower limb amputation

insulin-dependent, juvenile or thin

destruction of pancreatic ß cells (auto-immunity < 40 years)—>lack of insulin

10-15% of diabetes

↓ energy storage = weight reduction

↑ plasma FFA & ketone bodies (acidosis)

↑ glycemia —>glycosuria or glucosuria —> ↑ osmolarity —> cell dehydration —> polyuria, thirst, weight loss

non-insulin-dependent, adult, fat

defect in insulin cell response or insulin resistance (IR + insulin defect, after 40 years)

most of the time lined to obesity (>80%)

85-90% diabetes

fortuitous discovery

often long period without symptoms (insulin resistance compensated long) with increased level of insulin secretion

often associated with overweight (80%)

often associated with arterial hypertension & excessive [FFA & TG] in the blood

diagnostic of exclusion

high increase in northern countries

prevalence (total number of cases) & incidence (new number of cases per year) highest in europe

genetic susceptibility: inherited susceptibility (polygenic disease) but only 15% of relatives develop also T1D

something must set off the immune system causing it to turn against itself and leading to the development of T1D

environmental factors: trigger autoimmune process, role of virus suspected (high prevalence of T1D during rubella)—>direct cytopathogenic effect of the virus on ß-cells & role of some food substances

infiltration of macrophages and T lymphocytes within the islets inducing the complete destruction of ß-cells

markers: auto-antibodies—>anti-islets & anti-insulin

decreases in type 1a before 25 years

in type 1b decrease at around 35 years (associated with other auto-immune pathologies)

need at some point injection of insulin to survive

don’t know leading factor

interplay of genetics, environment, auto-antibodies

onset at different ages but same effect

life-threatening acute metabolic complication without injection of insulin (coma due to stress reaction)

increase of catecholamines & cortisol lead to infection & stress —> worsening of the process

AGE: advanced glycation end product

due to high glucose level non-enzymatic condensation reactions of glucose protein

formation & accumulation during normal aging and highly accelerated in T2D & Alzheimer's disease

high in North Africa/US, not too high in Europe

almost one in two adults with diabetes are unaware they have the condition

39% of the adult world population

has more than doubled since 1980

the first cause of the epidemic development of T2D

2 early metabolic defects present many years before appearance of the disease symptoms:

Insulin resistance: diminution of insulin effects in its targeted tissues (muscles, AT, liver) compensated by increased secretion in the beginning

insulinopenia: diminution of the insulin secretion ability by the pancreatic ß-cells

conjunction of numerous susceptibility genes whose expression depends on environmental factors (excessive consumption of saturated fat, sugar & sedentary life)—>polygenic disease

environmental factors: aging, stress, unhealthy diet, physical inactivity, intrauterine environment, obesity (BMI>30)

epigenetic factors: induced by environment —>DNA methylation, histone modifications, microRNAs

mutations in insulin gene (very rare)

mutations in mitochondrial DNA (mitochondrial diabetes very rare)

genes of the Maturity Onset Diabetes of the Young (MODY 1-5, MODY 2 50% of MODY mutations of the glucokinase gene) —>rare MODY = 5% of T2D

decreased insulin secretion & insulin resistance

leads to increased glucose hepatic production (fasting hyperglycemia) and decreased peripheral glucose consumption (muscle) post-prandial

—>hyperglycemia = diabetes

normally: ↑glucose—>↑ insulin —> ↑ storage of lipids & glucose & use of glucose inhibited, production of glucose

T2D: no increase in insulin & no inhibition of lipolysis —> ↑FFA in blood

liver: ↑ gluconeogenesis & de novo lipogenesis, decreased glycogen synthesis

everything pushed to increased glucose & FA in blood but inhibition of glucose use

quantitative: less mature insulin secreted due to defective maturation and secretion of inactive pro-insulin

qualitative: disappearance of the first peak of insulin secretion (normally prepares organism to answer & biphasic secretion)

increased ß-cell replication (try to compensate insulin resistance & more ß-cell neogenesis)

decreased ß-cell size

increased ß-cell apoptosis (inflammatory defect)

decreased cell mass: due to increased apoptosis & not enough neogenesis

at some point, not enough insulin is produced to compensate for resistance

At the point of diagnosis already 70-90% of ß-cell mass lost

unfunctional glycoproteins

high level of FFA leads to decreased insulin secretion

decreased number of Langerhans islets by apoptosis

constant demand for insulin leads to increased ER work and metabolic stress —>misfolding of proteins

—>stress

amylin secreted together with insulin

can build fibers —> protein plaque disturbs cell function —>more rigid

chronic metabolic stress leads to changes in the ß-cell (decompensation)

dedifferentiation to empty cells—>total dedifferentiation & no insulin production

ß-cell to α-cell conversion: transformed α-cell produces glucagon

defects of insulin receptor or its tyrosine kinase activity (PC-1 (inhibitor IR), TNF-ß, IRS-2)

↓ Glucose transporter (↓ number (reduced transcription) or translocation)

Phosphorylation of glucose (↓ HKII activity)

Synthesis of glycogen (↓ activity of glycogen synthetase & glucose uptake)

oxidation of glucose (inhibition by Randle’s effect)—>too many nutrients present in the blood

neoglucogenesis (activation of PEPCK, ↑ pyruvate)

adipose tissue (80% loss of GLUT4, lipolysis)

vascular endothelium (↓micro vascularization & blood flow)

Alteration of ß-cell—>↓glucose-induced insulin production —> increased glucose hepatic production —>hyperglycemia —>reinforces alteration of ß-cells

fasting hyperinsulinemia & hyperglycemia due to post-receptor anomalies leads to reduced insulin cell response —> ↓ glucose uptake —>reinforces hyperglycemia

hyperinsulinemia

defect in FFA storage by AT (loss of the ability to strongly suppress lipolysis + inadequate storage)—>increase in FAA

FFA mobilization leads to:

• increased FFA oxidation & decreased glucose consumption in muscles (more lipids than normally stored, ectopic fat accumulation)

• increased FFA oxidation & neoglucogenesis in the liver —>secretion insulin, VLDL-TG & glucose —>increased glycemia

stress receptor TLR4 stimulated by high level of FFA

production of JNK—>activates serine kinase—>phosphorylation of insulin receptor & IRS (inactivation)

alteration of FA oxidation: in the beginning lipids used to increase ß-oxidation, but with time mitochondria decrease ß-oxidation in obese patients

mitochondrial dysfunction: decreased number of mitochondria in muscle & decreased FA oxidation

ectopic storage in Diacylglycerol (instead of TG)

DAG activates PKC—>activation serine kinase —>phosphorylation IRS1 & other enzymes —>inhibits signaling (decreased glucose uptake & glycogen storage, increased gluconeogenesis)

accumulation of lipids in muscle & liver: not in AT —>increases insulin resistance

—>hypoinsulinemia: decreased insulin secretion

50% of ß-cell function is already lost

ß-cell function will continue to decline despite treatment

majority of patients will eventually require insulin therapy

need insulin resistance & exhaustion of ß-cells for diabetes

cardiovascular disease

neurodegeneration

cancer

BMI > 30 kg/m^2

39% of adults in the world population, has doubled since 1980

lower prevalence in Africa

increased obesity with time & age

inversely proportional to the level of education & income

more men with overweight, more women with obesity

anthropometric: waist size, waist-hip ration

skin fold measurement: under scapular, abdominal, triceps skin fold

gynoid: below the waist (pear), not a cardiovascular risk

android: above the waist (apple), numerous metabolic disturbances

genetic rare (adrenergic receptor, leptin receptor, uncoupling protein)

environmental: modifications of behavior (decrease of energy expenditure due to decreased physical activity in sedentary life & increased energy supply due to transformation of food habits)

induced by some drugs (antipsychotics, antidepressants, corticosteroids, ß-blockers, insulin)

1. desensitization (decreased insulin action)

2. leptin = adipostat (leptin resistance)

3. inflammation (increases insulin resistance)

4. counter-inflammation

negative feedback (mechanism of regulation induced by insulin)

receptor overstimulation leads to endocytosis & decreased activity

adipocytes sense size & lipids stores & secrete leptin

binds receptor in the hypothalamus to reduce appetite, activation of hepatic fatty acid oxidation while reducing lipogenesis & increasing sympathic activity

PI3K neuromediator in the brain

stimulation of anorexigenic signals (decrease appetite & increased energy expenditure & thermogenesis)

resistance due to problem of crossing the blood-brain barrier, loss of receptor activity & rarely mutations in the receptor

overstimulation of leptin receptor leads to overproduction of SOCS3

resistance

adipocytes continues to expand & store lipids after leptin resistance

release of chemkines like MCP1 —>recuritment of M1-polarized pro-inflammatory macrophages to AT—>secretion TNFα & IL6

toll receptors acitvated in response to local increases in FFA

inititation of MAPK pathway —>increases lipolysis & desenitizes insulin action

cell hypertrophy mechanical stress for surrounding cells—>macrophages infiltrate—>alteration of secretion—>pathological consequences / insulin resistance

hypoxia: hypertrophy changes O2 gradient & Hypoxia inducible factor 1 leads to release of MCP-1 —>attraction of macrophages

ER stress/UPR activation: unfolded protein response when chaperones not sufficient to ensure correct folding (normally stress sensor inactivated by chaperones)—>if not induction of gene transcription & NFκB signaling

intestinal microbiota:modification of the intestinal flora after high fat diet & associated mechanisms induce inflammation, diabetes & obesity—>theory of lipopolysaccharides (increased leak)

serine kinase phosphorylates receptor & IRS-1 —>inhibits insulin signaling—>resistance

anti-inflammatory role of IKKε & TBK1

but inflammation sustained and low grade (avoid apoptosis)

metabolic disorder: increased lipolysis & accumulation of FA

cytokine & inflammation sustained

would have positive action on metabolism

but downregulated

coma by acidoketosis/hyperosmolar

neuropathy & nephropathy

retinopathy (blindness without treatment)

angiopathy

but mainly cardiovascular complications

non alcoholic fatty liver disease prevalent in 10-33% worldwide

linked to insulin resistance, T2D & obesity (high prevalence in obese & diabetic patients)

have high prevalence of hypertension, dyslipidemia & hypercholesterolemia

new name: metabolic dysfunction-associated steatotic liver disease

fatty liver—>more than 5% of liver tissue occupied by lipids

inflammatory state—>defective function of the liver

cirrhosis (dysfunctional liver)

hepatocellular carcinoma

—>total dysfunctioning, need graft

vascular disease main reason of death

stable plaque: limits size of the vessel but no symptoms

fibrotic plaque: total closing of vessel, no blood flow /heart stops

ruptured plaque: develops inside the tissue (not visible with normal examination), rupture at some point, enters circulation & blocks vessel

inflammatory porcess due to excess of lipids in the blood (LDL) stresses endothelial cells—>enter intima—>oxidation LDL

recruition of macrophages—>secretion TNFα

phagocytosis of oxidized LDL

foam cells (macrophages full of lipids created)—>apoptosis

formation of necrotic core with many lipids that is stabillized by secretion of fibrin

at some point rupture—>contact of blood & insed of intima leads to formation of a thrombus & clotting of the vessel

coronarly diseases

heart attack

arteritis of lowe limbs

verebrovascular diseases

latent autoimmune diabetes in human

thought that T1D&T2D possess unique etiologies, disease courses & treatment approaches

but overlap (T1D also possible at later age & T2D at early age)

intermediary type