Patofyziologie - úbytek beta-buněk
Toxoicita vůči beta buňkám
- Rizikové faktory vzniku diabetu
- Příčiny poklesu masy beta buněk
Ki67 (a marker of proliferation)
- All individuals had a low frequency of replication
- There was a trend toward decreased beta cell replication with age
- When normalized for beta cell mass
- 3x and 10x increase in beta cell apoptosis in obese and lean diabetic individuals
- Compared to obese and lean non-diabetic individuals
- Balance of replication and apoptosis is important
- Decline in beta cells in the elderly
- Inadequate proliferation / elevated apoptosis [65]
Autoimmune reaction in T1D
- ß-cell proliferation
- Increased during the pathogenesis of diabetes 1
- Does not adequately compensate for autoimmune-mediated destruction [14]
- T-cell-mediated autoimmune disease
- Selective destruction of pancreatic ß-cells:
Infiltration of inflammatory cells
- Subsequent insulitis
- Direct contact
- T helper type 1 (Th1) cells
- Macrophages
Proinflammatory mediators in DM1
- Exposure to soluble mediators secreted
- Oxygen free radicals [14]
- NO
- IL-1ß, IFN- alfa and TNF-alfa
- Major soluble factors which mediate ß-cell damage
- Response to the stimulation of IL-1ß and INF- alfa around 700 genes are up- or down-regulated in ß-cells [14]
Faktory zánětlivé obecně
- Nejen při DM1, ale jakémkoliv zánětu
- Cytokines and hyperglycemia
- Share some common mechanisms to alter ß-cell gene expression
- C-Myc, A20, and heme-oxygenase are induced [14]
Interleukin-1ß (IL-1ß)
- Activate transcription factor nuclear factor (NF)-kB
- Activation of NF-kB
- Common and crucial step for various cytokine-stimulated ß-cell dysfunction
- Overexpression of iNOS in ß-cells - produce massive amounts of NO
- Cytotoxicity to ß-cells [14] !!!
- Important role for NO in the pathogenesis of diabetes !!!
- Decreased expression levels of transcription factors responsible for ß-cell differentiation and function
- PDX-1
- Isl-1 [14]
- Overexpressing iNOS
- Transgenic mice - in ß-cells developed insulin-dependent diabetes
- Inhibition or knockout of iNOS
- In the islets protects ß-cells in vitro and in vivo from the cytotoxic effects of cytokines [14]
- Basal activity of NF-kB
- Required for maintaining ß-cell normal insulin secretary function
- Excessive activated NF-kB
- Up-regulates monocyte chemoattractant protein-1 (MCP-1)
- Down-regulates the Ca2+ pump sarcoendoplasmic reticulum Ca2+ ATPase type 2b (SERCA-2b)
- Leads to ER calcium depletion
- Severe ER stress which results in ß-cell apoptosis [14]
- Activates the c-Jun NH2-terminal kinase (JNK)
- A member of the mitogen-activated protein kinases (MAPKs)
- Cell-permeable peptide inhibitors of JNK prevent cytokine-induced ß-cell apoptosis
Interferon-alfa (IFN-alfa)
- Synergize with IL-1ß to trigger ß-cell apoptosis
- Binds to cell surface receptors and activates JAK1 and JAK2
- Phosphorylate the transcription factor STAT-1
- Including up-regulating iNOS expression [14]
Tumor necrosis factor-alfa (TNF-alfa)
- Snižuje v ostrůvcích Bcl-2
- Indukuje iNOS
- Jakákoliv infekce cestou aktivace TNF alfa a syntézy CRP
- Může vést ke spuštění dalších mechanismů poškozujících beta-buňky (přehled Anděl, 2009) [57]
Hypoglykemie
- Apoptózu beta-buněk indukuje nejen hyperglykemie ale i hypoglykemie
- Pro optimální funkci beta-buněk je nezbytná pravidelná stimulace fyziologickými koncentracemi glukózy [57]
Hyperglycemia
- Increase the production of IL-1 ß from ß-cell [14]
- Increase in ß-cell oxidative stress
- From the mitochondrial electron transport chain
- ER stress [14]
- Elevation of cytosolic calcium concentrations [14]
- Precedes conditions for lipotoxicity
- Glucotoxicity can occur independently of lipotoxicity [14]
- Excessive nutrients in T2D
- Chronic exposure to glucose leads to:
- Increases in cytosolic calcium
- Induce ß-cell destruction
- Leads to increased production of IL-1ß
- Subsequent NF-kB activation
- Increases in FAS
- DNA fragmentation
- Damaged ß-cell function [14]
- Constant entry of glucose into the ß-cell leads to:
- A state of reversible insensitivity to glucose stimulation
- Concomitant with an exhaustion of ß-cell stores [14]
- Defects in insulin production
- Chronic glucose exposure-induced ß-cell exhaustion becomes irreversible [14]
- Longstanding T2D (>15 years), ß-cell mass is reduced by over 50 % [17]
- Depressed rates of insulin synthesis
- Increased small heterodimer partner (SHP) nuclear receptor mRNA
- Downregulation of glucokinase mRNA
- Affect posttranscriptional processing of PDX-1 mRNA
- Changes in PDX-1 expression and activity
- Profound influence on insulin transcription [14]
- Less reversible effects on ß-cell function
- Particularly in regards to insulin synthesis [14]
- Reduced PDX-1 mRNA [14]
- Upregulation of the SHP receptor
- Competitive inhibitor to prevent p300-mediated PDX-1 and BETA2 complex formation
- Reduced protein and insulin promoter binding activity
- Compromised mitochondrial function
- Induction of apoptosis
- Repeated exposure to elevated glucose also
- Short-term excess levels of glucose
- Reversible glucose desensitization
- Effects on function rather than simply apoptosis [14]
- Excessive glucose stimulation
- Decrease FLIP
- ß-cell production of interleukin (IL)-1ß
- Followed by Fas upregulation
- Molecular link between type 1 and type 2 diabetes [64]
- IL-1ß is found in the ß-cells of type 2 diabetic patients
- Concomitant induction of Fas
- Decrease in FLIP protein expression [64]
- In vitro a 4-day exposure of human islets to elevated glucose concentrations
- Almost complete ablation of ß-cell secretory function
- <1% of ß-cells are apoptotic [64]
- Excess glucose and free fatty acids
- Generate intermediates that may change how glucose and fatty acids are metabolized
- Long-chain acyl-(coenzyme A) CoA
- Ceramides
- Cause oxidative stress and dysfunction [66]
Glycation reactions and production of ROS
- Non-enzymatically
- Alter the function of a variety of molecules
- Advanced glycation end products (AGEs)
- Implicated in cellular damage
- Insulin and glucokinase promoters sensitive to glycation
- Sensitive to the presence of ROS (superoxide, hydrogen peroxide, nitric oxide, hydroxyl radicals) [14]
Endogenní AEGs
- Vznik při hyperglykémii
Exogenní AGEs
- Konzumujeme s potravou - maso, mléko, káva, sýry [57]
- Zejména pokud je jejich příprava za vysokých teplot [57]
- Vznikají i během dlouhodobého skladování [57]
- Ke vzniku může přispívat i obsah aditiv [57]
- V myším a krysím modelu vede vyšší příjem AGEs¨ke:
- Zvýšené tvorbě superoxidu v mitochondriích
- Zvýšené apoptóze beta-buněk [57]
Aminoguanidine
- Glycation-inhibitor and antioxidant
- Prevents formation of AGEs and ROS !!!!
- Able to partly ameliorate the effects of those damaging compounds on ß-cell function !!! [14]
Hydrogen peroxide-scavenging N-acetyl-L-cysteine
- Podobné beneficial effect of the on insulin expression and secretion in db/db mice or Zucker rat ß-cells subjected to oxidative stress [14]
8-hydroxy-2'-deoxyguanosine (8-OHdG)
- Oxidative stress marker
- Elevated in ß-cells from diabetic Goto-Kakizaki (GK) rats [14]
Oxidative stress
- Process of aging - long-term exposure to ROS [14]
- Elevated levels of oxidative stress markers in the blood and urine of T2D patients
- Increased flux of glucose and fatty acids
- Tremendous burden on mitochondrial oxidation
- Increased membrane potential
- ROS production
- ß-cell has a limited ability to cope with oxidative stress
- Apoptotic pathways converge in the mitochondria with
- Caspase-3 activation
- Cytochrome C export
- Reduced glutathione (GSH) in blood cells in DM2
- Fructose, D-ribose and 2-deoxy-D-ribose redukují glutathion více než glucose [14]
Antioxidační enzymy
- ß-cell expresses relatively low levels of antioxidant enzymes = vulnerable to oxidative stress
- Cu/Zn superoxide dismutase (Cu/Zn-SOD)
- In the cytosol
- Generation of hydrogen peroxide from the reaction of superoxide and hydrogen
- Mn-SOD
- Functions in the mitochondria
- Generation of hydrogen peroxide from the reaction of superoxide and hydrogen
- Catalase
- Glutathione peroxidase (GPx) [14]
- Reduce hydrogen peroxide to water with GSH [14]
- GSH - glutathion vzniká z N-acetylcysteinu
- Reduce lipid peroxides to alcohols
- Oxidized GSH (GSSG) can be converted back into GSH
- By GSH reductase
- Using NADPH as a cofactor [14]
- Buthioinine sulfoximine
- An indirect inhibitor of GSH synthesis
Islet ROS
- Levels were correlated with glucose concentration [14]
- Glucose toxicity increases intraislet peroxide levels [64]
- Hydroxyl radicals
- Particularly dangerous in ß-cells
- Ability to cross the nuclear membrane
- Exert a mutatagenic effect [64]
Nadbytek glukózy a produkce ROS
- Oxidative phosphorylation as well as other pathways for glucose when glycolytic enzyme activity becomes saturated:
- Generates ROS
- Glycosylation (Schiff reactions)
- Autooxidation
- Glucosamine pathway (O-linked glycosylation of proteins)
- Activation of JNK and NF-kB is also stress-induced
- Phosphorylates the Ser307 residue of IRS-1
- (intracellular tyrosine kinase substrates that are downstream of their receptor)
- Leading to decreased nuclear PDX-1 [64]
- IRS-1 and IRS-2 - important for ß-cell function and survival
- Absence leads to insulin resistance
- The insulin-insulin receptor (IR)-IRS-PI3K-Akt signaling cascade is crucial for regulating islet cell differentiation and function
- Decreased IRS-2 levels and increased ß-cell apoptosis
- GLP-1 receptor activation in ß-cells leads to IRS-2 and PKB activation mediated by CREB and transactivation of EGFR [14]
Treatment with antioxidants:
- Improves glucose levels by reducing apoptosis rates
- Improving insulin gene expression, insulin secretion
- Pdx1 binding to the insulin promoter
- Myší model
- Reversing beta cell oxidative stress by glutathione peroxidase over-expression
- Restored MafA expression [64]
- Improved beta cell volume and glucose homeostasis [64]
Free fatty acid (FFA) - lipotoxicita
- Risk factor for ß-cell destruction
- Glucose and fatty acids - “glucotoxicity” and “lipotoxicity”
- Transient exposure of islets to free fatty acids (FAAs)(e.g., hours) can augment GSIS
- Long-term exposure (e.g., days) decreases insulin secretion [14]
- Increased lipolysis in white adipose tissue
- As a result of insulin resistance
- Amplified with body weight gain and continuous accumulation of adipose tissue
- Results in elevated circulating levels of free fatty acids
- Negative effect on GSIS
- Exacerbate insulin resistance in muscle and liver cells
- FA can directly cross the lipid-bilayer and act intracellularly
- Ability to activate the cell-surface receptors
- Such as GPR40
Form of lipid has a profound effect on ß-cell function:
Triglycerides (TGs)
- Relatively non-toxic
Nenasycené mastné kyseliny
- Inibují toxické účinky saturovaných FFA i v případě, že:
- Jsou přítomny v několikanásobně nižší koncentraci [57]
- Jsou přidány až po několika h působení nasycených MK (Welters et al., 2004; Morgan a Dhayal, 2010; Fürstová et al., 2011; Němcová-Fürstová et al., 2011) [57]
Monounsaturated fatty acids
- Such as oleate, kyselina palmitolejová [57]
- Are protective due to their propensity for esterification into TGs
- Protect ß-cells from palmitate and high glucose-induced ß-cell apoptosis [14] !!!
- Similar effects are also observed in non–ß-cells such as cardiac cells [64]
Trans-nenasycené MK - kyselina elaidová
- Snižuje proliferaci beta-buněk
- Anti-apoptotický účinek je nižší v porovnání s jejich cis protějšky (Fürstová et al., 2008; Dhayal et al., 2008).
HDLs
- Are protective
Saturated fatty acids
- Such as palmitate, starová MK, oxodované LDLs [57]
- Highly toxic at long-term exposure
- Induce cell death
- Palmitát
- Vedl ke zvýšení aktivity oxidázy nikotinamid adenin dinukleotid fosfátu (NOX) a NOX2
- Patologický zdroj volných kyslíkových radikálů (ROS) v beta-buňkách
- Zvýšil v buněčné membráně beta-buňky hladinu proteinu p47phox
- Regulační protein NOX2 [57]
- Suprese proteinu p47phox vedla k
- Poklesu palmitátem zvýšené produkce ROS
- Zlepšení palmitátem zhoršené glukózou stimulované sekrece inzulinu (Sato et al., 2014) [57]
Glucolipotoxicity
- Inhibition of ß-oxidation
- Stimulation of complex lipid formation
- mitochondrial and ER stress
- High glucose levels prevent metabolism of fatty acids which
- Results in funneling to pathways involving formation of toxic compounds (e.g., ceramide)
- Down-regulate insulin, cause ß-cell dysfunction, and results in apoptosis [14]
- The chronic exposure of cells to glucose and fatty acids
- Places a tremendous metabolic burden on the mitochondria and ER
- Glucose metabolism in the ß-cell
- Leads to formation of citrate
- A signal for formation of malonyl-CoA in the cytosol
- Inhibits carnitine palmitoyl transferase-1 (CPT-1) activity (key role in transporting fatty acids into the mitochondria)
- Blocking fatty acid ß-oxidation
- Accumulation of long-chain acyl-CoA esters in the cytosol
- Activation of AMP-activated kinase (AMPK)
- Inversely correlated with glucose concentration
- Enhanced by fatty acids in ß-cells [14]
- Leads to lipogenesis
- Via transcription factor sterol-regulatory-element-binding-protein-1c (SREBP1c) [14]
Lipotoxicity of FFA - complex - mechanismy lipotoxicity might occur:
repeated exposure of ß-cells to fatty acids:
- Změna exprese pro- a antiapoptotických proteinů rodiny Bcl-2 (Gurzov a Eizirik, 2011) [57]
- Indukce tvorby ceramidu (Galadari et al., 2013) [57] [14]
- Indukce ROS (Pi a Collins, 2010) [57] [14]
- Apoptóza (Las a Shirihai, 2010) [57]
- Inflammatory response
- Accumulation of adipose tissue
- Sekrece TNF-alfa, IL-6, leptin, resistin and adiponectin, FFA [14]
- Can be cytotoxic to ß-cells [14]
- Changes in insulin granule secretory machinery
- Dissociation of insulin secretory granules from voltage-gated Ca2+channels
- Dampens GSIS
- Reduces nuclear translocation of PDX-1
- Red. expression of MafA
- Down-regulates insulin expression
- Induces apoptosis
- Activation of PLC [14]
Stres endoplazmatického retikula (Biden et al., 2014)
- Po narušení funkce ER nejprve aktivována kaskáda signálních drah
- K obnovení syntézy sekretovaných proteinů
- Včetně inzulinu
- V případě neúspěchu této odpovědi
- Indukce apoptózy
- Level where FFAs are esterified
- Increased insulin demand (high glucose) = ER stress induced by FFA might be amplified [14]
- To reduce the burden on the ER
- High demand for insulin = + metabolismus induce ER stress markers including:
- Impair ER calcium handling [14]
- PERK
- Phosphorylation of eIF2a
- Mediates a reduction in ER load
- Responsible for the initial response of temporarily halting protein translation
- Halting entry into the ER to prevent overloading [14]
- Increase in translation of the bZIP transcription factor ATF4
- Leading to an increase in transcription of proteins that aid in cell recovery:
- C/EBP homologous protein (CHOP; GADD153)
- GADD34 [14]
- Interferon response element (IRE)-1/X-box binding protein (XBP)-1 (alternative splicing of XBP-1)
- IRE1 is a kinase/endoribonuclease that splices XBP-1 mRNA
- Activating transcription factor (ATF)-6
- Unfolded protein response (UPR) activate:
- Misfolded proteins
- Targeted for degradation by ubiquitination in the cytosol [14]
- Apoptosis is induced if:
- Response is insufficient to attenuate the accumulation of misfolded proteins
- ER function is compromised [14]
Mitochondrieální ox. stres
- Upregulation of the mitochondrial inner membrane protein uncoupling protein 2 (UCP2)
- Activation of UCP2 by ROS
- Can dissipate the membrane potential by allowing protons to leak into the mitochondrial matrix
- Couple the oxidation of fuel to heat rather than ATP
- In islets from human donors with T2D as well as ob/ob mice, UCP2 was up-regulated
- Protective effect against generation of ROS [14]
- Reduction in ATP production and hence decreased ATP/ADP ratio leads to reduced insulin-secretory capacity
- Leading to decreased ATP production
- And induction of the unfolded protein response
- May all be central to the series of events leading to apoptosis [14]
- Deletion of the UCP2 gene as well as reduction of endogenously produced superoxide in the mitochondria
- Restored islet ATP levels and enhanced GSIS [14]
- C57BL/6J mice
- Fed a high-fat diet for 12 wk
- 60 % increase in mitochondria mass (objem, ne počet) [14]
- Mice with a 5-exon deletion in nicotinamide nucleotide transhydrogenase (nnt)
- Enzyme of respiratory chain, converting NADP+ and NADH into NADPH and NAD+
- Impaired glucose clearance, and lack of GSIS [14]
- ROS/aging-associated
- Increases in mitochondrial DNA (mtDNA) mutations
- Increased susceptibility of the ß-cell to metabolic overload [14]
Mitochondrie
- Central role of the mitochondria in insulin secretion and insulin sensitivity [64]
Mitochondrial dysfunction
- Proposed as a common feature
- Impaired insulin responsiveness of peripheral tissues [64]
- Defective ß-cell secretory function and survival [64]
Pancreatic duodenal homeobox gene-1 (PDX-1)
- Regulates insulin secretion via mitochondrial effects
- Critical regulator of ß-cell survival [64]
Mitochondrial uncoupling protein-2
- In insulin secretion is well established [64]
Glukagon
- In T2D
- Marked increase in glucagon secretion at high glucose
- Exacerbates the hyperglycemic effects of insulinopenia
- Too little glucagon secretion at low glucose
- May precipitate fatal hypoglycemia [17]
- Mice with glucagon receptor genetically ablated [17]
- Complete destruction of the ß-cells by streptozotocin does not result in hyperglycemia [17]
- Expression of the glucagon receptor in the liver alone
- Is sufficient to produce severe diabetes in glucagon receptor-null mice lacking functional ß-cells
- Suppression of glucagon-induced hepatic glucose output
- Would appear to be a good target for T2D therapy [17]
- Metformin, widely used to treat T2D (especially in the obese)
- Lower blood glucose by antagonizing glucagon action and lower hepatic gluconeogenesis
- V.s. via reduced cellular metabolism:
- Inhibition of adenylyl cyclase
- Inhibition of cyclic AMP production [17]
- Glucagon receptor antagonists improve glycemia in T2D
- Glucagon-like peptide 1 (GLP1) mimetics
- Improve glucose homeostasis, at least in part, by reducing plasma glucagon levels [17]
- Inhibitors of dipeptidyl peptidase 4
- DPP4 is the enzyme that inactivates GLP-1
- Improve glucose homeostasis, at least in part, by reducing plasma glucagon levels [17]
- Reduced hepatic glucose output
- May also be part of the reason why excellent diabetes control can be rapidly achieved (prior to substantial weight loss) by a very low calorie diet [17]
- Too much glucagon + too little insulin = increased plasma glucose production [19]
- Glucagon maintain a steady level of blood sugar level between meals [19]
- Glucagon stimulates
- Insulin secretion [19]
- Somatostatin inhibits
- Insulin secretion
- Glucagon secretion [19]
- Fasting glucagon was higher in T2DM compared to NGT and IGT [21]
- Dysregulated glucagon secretion in response to glucose or the amino acid arginine
- Evident in postmenopausal White women several years before diagnosis of IGT [21]
- Insulin-AUC 0–30 min and glucagon-AUC 0–30 min
- Almost equivalent contributions of impaired insulin and glucagon secretions in hyperglycemia after ingestion of glucose or meal [21]
- DM2
- Pancreatic cells secrete too little or no insulin at all [43]
- Pre-diabetes
- Ingestion of glucose
- Suppressed glucagon in NGT and IGT
- Glucagon was increased in T2DM = "paradoxical rise of glucagon after ingestion of glucose in T2DM" [21]
- Ingestion of mixed meal
- Significantly increased glucagon in all groups
- Glucagon remained significantly higher in T2DM [21]
Sekrece glucagonu
Stimulována
- Low levels of glucose in the blood [19]
- Neuroregulace alfa buněk
- Prakrinně ze sousedních beta buněk, které vlivem glukózy vylučují
- Inzulin
- Alfa aminobutyric acid
- Zinc
- Glutamate [19]
- Arginine, alanine, and glutamine - potent stimuls
- Most glucagon release after protein intake
- Chronic elevation of fatty acids [21]
- GIP enhances glucagon secretion [21]
Inhibována
- High levels of glucose
- Amylin [19]
- Somatostatin
- GLP-1 suppresses glucagon [21]
Closure of the KATP channels
Sulfonylureas tolbutamide, glibenclamide
- May induce Ca2+-dependent ß-cell apoptosis in rodent and human islets
- Observed only in vitro and not consistently [64]
- Recent clinical study comparing insulin and sulfonylurea treatment of DM2
- Treatment with insulin preserved ß-cell function more effectively than glibenclamide [64]
- Is it beneficial effects of insulin / the possible ß-cell toxicity of glibenclamide ? [64]
- Deterioration of insulin secretion
- Was seen in patients treated with sulfonylureas in the U.K. Prospective Diabetes Study [64]
- Those treated with insulin were not evaluated in this regard [64]
Leptin
- Adipocyte-derived satiety factor
- Pro-inflammatory cytokine
- Structural similarity with other cytokines
- Receptor-induced signaling pathways [64]
- Accelerates autoimmune diabetes in NOD mice
- Providing an additional link between type 1 and type 2 diabetes [64]
- Promotes other autoimmune diseases
- Inflammatory bowel disease
- Multiple sclerosis
- Rheumatoid arthritis [64]
- Induces ß-cell apoptosis via:
- Increasing release of IL-1ß
- Decreasing release of the IL-1 receptor antagonist [64]
Amylin
- Peptide of 37 amino acids neuroendocrine hormone
- Islet amyloid polypeptide (IAPP) or amylin [65]
- Co-secreted with insulin from the beta cell [65]
- Inhibits the secretion of glucagon;
- Slows the emptying of the stomach;
- Sends a satiety signal to the brain [65]
- Tend to supplement actions of insulin, reducing the level of glucose in the blood [65]
- Synthetic, modified, form of amylin (pramlintide or Symlin®) [65]
- Used in the treatment of DM2 [65]
- In DM2 - hypersecretion of insulin
- Increased co-secretion of amylin
- Aggregates into amyloid plaques [65]
- Více než u >90% DM2 [65]
- Can subsequently lead to increased beta cell apoptosis
- Can cause progression of diabetes
- With age there is an increased deposition of amylin of DM2, u zdravých [65]
- Rodent amyloid
- Does not aggregate due to a proline amino acid substitution
- Transgenic mice were developed that expressed human (h)IAPP
- Over-expression of hIAPP resulted in hyperglycemia
- Hyperglycemia preceded the formation of obvious plaques [65]
- Could be, at least in part, due to cytotoxicity from intermediate-sized amyloid particles [65]
- Freshly dissolved hIAPP exogenously to dispersed mouse and human islets
- Silet cell apoptosis and necrosis occurred within 24 to 48 hours [65]
- Intermediate-sized amyloid particles
- Caused membrane damage and subsequent cell death
- Increases in amylin deposition size can cause increased beta cell death and progression of DM2 [65]
p16
- Gene named p16
- Activate a program called senescence in cells
- Prevents cells from dividing
- Important in preventing cancer
- Increases in human and mouse pancreatic beta cells during aging
- Limits their potential to divide
- The lack of ability of these cells to divide can contribute to diabetes [17]
Pancreatectomie
- 60 % pancreatectomie
- Do not always develop hyperglycemia
- Are able to compensate by enhanced functionality in remaining ß-cells [14]
Organická rozpouštědla
Perchlorethylen
Benzín aj.
Fluor a floridy
Produkty spáleného jídla
Hypoxie
- Beta-buňky jsou výrazně citlivé na hypoxii
- Myš exponovaná intermitentní hypoxii
- Má poruchu sekrece inzulinu
- Zhoršení citlivosti k inzulinu
- Normalizací přívodu kyslíku, dojde také k částečné úpravě těchto poruch (Polák et al., 2013)
- Spánková apnoe u obézních
- Jedním z faktorů (Pallayová, 2011; Mesarwi et al., 2013)
- Hypoxie Langerhansových ostrůvků vede
- V beta-buňkách k významnému nárůstu apoptózy
- V alfa-buňkách ostrůvků apoptóza výrazně nenarůstá (Bloch et al., 2012) [57]
Železo
- Dlouhodobé expozici železu
- Geneticky hemochromatóza
- Transfuze opakov.
- Hepatitis C
- Porphyria cutanea tarda
- Depozice železa v pankreatu
- Sekundární fibróza
- V desítkách % případů k diabetu (Garger et al., 2010)
- Oxidační poškození z volných kyslíkových radikálů
- Derivovaných právě z účinku nadbytečného železa (Swaminathan et al., 2007). [57]
NF-kB
- Low-grade inflammation
- In the liver DM2
- Contributing to insulin resistance
- May influence peripheral insulin resistance via actions in myeloid cells [64]
- Nonsteroidal anti-inflammatory drugs
- Enhance insulin sensitivity
- Protect the ß-cell from apoptosis
- Via inhibition of NF-kB [64]
- May have a key role in causing both insulin resistance and impaired insulin secretion in DM2 [64]
- Hyperglycemia and free fatty acids
- Induce activation of NF-kB
- Inhibits glucose-stimulated insulin secretion in pancreatic ß-cells [64]
POPs - perzistentní organické polutanty
- Polychlorované či polybromované uhlovodíky (PCB, DDT...)
- Primárně se ukládají v tukové tkáni
- Permanentně ve velmi malém množství uvolňovány do krevního oběhu
- Koncentrace různých POPs v krvi a/nebo v tukové tkáni
- Pozitivní korelace s výskytem diabetes mellitus
- (Codru et al., 2007; Cox et al., 2007; Son et al., 2010; Everett a Matheson, 2010; Everett et al., 2011; Crinnion, 2011; Gasull et al., 2012).
- Zdroje
- Běžně používané maso ryb s vysokým obsahem tuku
- Losos (Crinnion, 2011)
- POPs ve stravě myší a krys (dle druhu, délky expozice a koncentrace POPs)
- Signifikantní změny v metabolismu glukózy
- Nárůst obezity a inzulinorezistence (Ibrahim et al., 2011; Ruzzin et al., 2009)
- Hyperinzulinemie (Gray et al., 2013)
- Hyperglykemie nalačno (Howell et al., 2014)
- Lidé přijímají POPs celý život, nepravidelně a nerovnoměrně ve velmi malých dávkách, které se kumulují
- Lidské pankreatické beta-buňky NES2Y subletální koncentraci DDT po dobu 1 měsíce
BPA, PCBs
- Found to increase insulin secretion
- Damage the beta cells [59]
Arsenic
- Damage the beta cells [59]
Mercury
- Impair insulin secretion [59]
- Damage the beta cells [59]
- Associated with impaired insulin secretion in humans (e.g., persistent organic pollutants)
Phthalates
- Developmental exposure
- Multiple effects on beta cells and the pancreas in animals [59]
Estrogenic compounds
Bisphenol A
Organophosphorous pesticides
Streptozotocin
- Induktory diabetu 2. typu v experimentálním krysím a myším modelu
- Vede k trvalejším hyperglykemiím než aloxan
- Může tak být snadněji použit pro studium vzniku komplikací (Christopher et al., 2010)
- STZ causes fragmenting DNA (Lenzen 2008)
- V experimentu se tomuto účinku dá zabránit nikotinamidem [59]
- Also causes autoimmunity in primates (Wei et al 2011)
Alloxan
- Accumulate in beta cells
- Interfere with insulin secretion
- Eventually kill the beta cells
- Causes oxidative stress that kills the beta cells
Vacor
- Jed na krysy
- Now-banned rat poison
- Known to cause type 1 diabetes in humans
- By killing beta cells
- Linked to type 1-related autoimmunity in humans (Karam et al 1980) [59]
- Na bázi N-3-pyridylmetyl-N-p-nitro-fenylurey (PNU, pyriminil)
- Ať již při náhodné, nebo suicidální expozici
- Způsobil několik desítek případů těžkého inzulin--dependentního diabetu s ketoacidózou
- S pozdějším rozvojem autonomní a periferní neuropatie
- Látka přímo toxická pro beta-buňky
- V experimentu se tomuto účinku dá zabránit nikotinamidem [59]
- Léčba nikotinamidem při otravě Vacorem však nerevertovala diabetes (Pont, 1979; Karam et al., 1980; Johnson et al., 1980)
Pentamidin
- Antimikrobiální prostředek
- Antipararazitikum
- Pneumocystová pneumonie
- V případech, že selhala terapie Biseptolem
- Zejména u nemocných s HIV [57]
- V týdnech - měsících po zahájení léčby se u 70–100% rozvine ireverzibilní inzulin-dependentní diabetes (přehled Anděl et al., 2011) [56]
- Leishmanióza [57]
Antidepresiva typu SSRI
Fluoxetin (Prozac)
- V léčbě deprese aj.
- Selektivním inhibitorem reuptake serotoninu (SSRI)
- T.č. nejvíce předpisovaná skupina antidepresivních léků [57]
- Bu. krys zvýšená produkce ROS
- V.s. snížení aktivity mitochondriálního elektronového transportního řetězu (ETC) [57]
- Fluoxetin vede k poklesu glukózou stimulované sekrece inzulinu (GSIS)
- Deficit byl preventabilní přidáním kyseliny listové (De long et al., 2014) [57]
MODY typy diabetu
- Faktory spojené s poruchou sekrece inzulinu [57]
Faktory virové
Coxsackie viry
Virus chřipky H1N1
Enteroviry
Kouření
Nádorová infiltrace
Vazivová infiltrace
Chronická pankreatitis
Zahájení apoptózy beta buněk
Intrinsic pathways
- Activated by stress factors including
- Growth factor deprivation
- Cell cycle disturbance
- DNA damage
- Lead to mitochondrial release of cytochrome c
- Subsequent stimulation of caspase-9 [96]
Extrinsic pathways
- Begins with cell death receptors
- Associated activation of caspase-8
Společné cesty
- Both pathways stimulate effector caspases (3, 6, and 7)
- Target the substrates that promote
- DNA fragmentation
- Cell death (Sharma et al., 2009; Forouzanfar et al., 2013) [96]
Oxidative stress
- An important role in beta cell dysfunction and apoptosis (Yang et al., 2011)
- Because of poor antioxidant capacity, beta cells are vulnerable
- Induced by both T1D insulitis and T2D glucotoxicity (Sharma et al., 2009)
Drugs and phytochemicals
- That improve glycemia and/or oxidative stress
- Ameliorate or prevent islet lesions
- Protective effect of some phytochemicals on pancreas has been found to be mediated through their antioxidant effects
- More effective ones even modulate / stimulate regeneration pathways of beta cells [96]
- Patients at the earliest stages of diabetes can be treated with these plants to delay or prevent the full destruction of pancreatic islets [96]
- Construction of polyherbal compounds through the combination of these phytochemicals
- May yield more potent regenerative agents for beta cells [96]
