MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

J - Inhibice sekrece inzulínu

Potlačení sekrece inzulínu

  • Může být v některých případech výhodné stran hubnutí
    • Méně pocitů hladu, lipolýza v tukové tkáni
    • Ideální je dosáhnout snížení sekrece nikoliv funkční poruchou, ale snížením objemu potravin
  • V případě, že je snížená sekrece inzulínu doprovázena hyperglykémií, situace se stává toxická
  • Pokud je sekrece inzulínu snížená v důsledku nevratného selhávání funkce slinivky a úbytku beta-buněk, je situace přímo fatální
    • A vede k postupnému vzniku diabetu mellitu s nutností užívání inzulínu

Pokles glukózy v plazmě

  • Stupá
    • Glukagon
    • Somatostatin
    • Ev. stresové hormony
  • Obnovuje se rovnováha
    • glykémie normálně neklesne pod dolní hranici normálních hodnot
  • Pokles glukózy v krvi - pod 4,6 mmol/l
    • Registrace recept. v CNS
      • Aktivace sympatiku
        • Adrenalin z adrenal glands and noradrenalin from sympathetic nerves [1]
          • Především noradrenalin během stresu silně inhibits insulin secretion[15]
            • Inhibiční alfa-2-adrenergní receptory [15]
              • Dominují nad stim. alfa-1-adrenergními rec. v pankreatu [15]
                • glykemie neklesne during exercise / the ‘fight-or-flight’ response [17]
    • Somatostatin (SIH) z buněk pankreatu [1]
    • Galanin (neuropeptid) [1]
  • glykémie pod 3,8 mmol/l
    • Sekrece kortizolu, adrenalinu a růstového hormonu
  • glykémie pod 2,8 mmol/l
    • Kognitivní dysfunkce
  • glykémie 0,6 mmol/l
    • Trvalé poškožení mozku, smrt [1]

Dlouhodobá expozice volným MK

  • Sekreční stimul natolik výrazný, že se dostavuje hyperinzulinémie
    • Dokonce vyšší, než by odpovídalo hladině glukózy [10]
  • Počáteční hyperinzulinémie se kombinuje s inzulínovou rezistencí, která se zvýrazňuje
  • Současně se tlumí sekrece inzulínu stimulovaná glukózou [10]
  • Dlouhodobá expozice zvýšené hladině MK má na sekreci inzulínu opačný efekt než krátkodobý vzestup [10]
  • Snižuje se exprese genu pro inzulín [10]
  • Postupně negativní účinek chronicky zvýšené hladiny volných MK na sekreci inzulínu
    • následně vznik hypoinzulinémie [10]
    • Selhání funkce slinivky [10]
    • Ukládáním lipidů (především triacylglycerolů) ve svalové tkáni, játrech a v B-buňce [10]
    • Lipotoxicita a glukotoxicita [10]
    • Zvýšená apoptóza v Langerhans. ostrůvcích
    • Spouštěč apoptotického programu ß-buněk
      • Prohlubuje změny způsobené inzulínovou rezistencí v periferních tkáních [10]
      • Rozvoj diabetu 2. typu i jeho postupné zhoršování [10]

Volné MK - metabolismus v beta buňkách

  • Vstupují do B-buňky / játer a svalu
    • Nejsou oxidovány v mitochondriích beta-oxidací
      • Blokován jejich transportní enzym karnitin-palmityltransferáza (CPT-1) malonylkoenzymem A
        • Aktivní forma volných MK (acylkoenzym A) se využije k syntéze triacylglycerolů [10]
  • Zvýšené množství MK uvnitř buňky + diacylglycerol (DAG)
    • Tlumí metabolismus glukózy
    • Prohloubí inzulínovou rezistenci [10]
  • Molekula DAG (di-acyl-glycerol)
    • Stimuluje aktivity proteinkináz C (PKC)



Melatonin

  • melatonin receptor (MTNR) 1B
    • Is coupled to Gi
      • Inhibits G protein
        • Decreased cGMP levels inhibit insulin secretion [14]
  • Activation of melatonin receptor
    • Inhib. activation of adenylate cyclase to catalyze cAMP production [14]
      • Blocks the enhanced insulin secretion by cAMP agonists
        • Forskolin
        • GLP-1 [14]
  • Circadian oscillation of the ß cell transcriptome
    • About 27% [19]
      • proteins involved in the assembly, trafficking, and membrane fusion of vesicles
        • Participate in insulin secretion [19]
    • Glucagon
      • Glucose levels in the blood are sufficient when we do not eat
        • For instances during the night [24]
  • Spánková restrikce u mužů proti normálně spícím zdvojnásibila:
    • insulin sensitivity decrease
      • With no compensatory increase in insulin secretion [40]
    • Markers of inflammation increased
  • Circadian misalignment that occurs in shift work may increase diabetes risk and inflammation
    • Independently of sleep loss [40]
  • Inhibitory effect
    • Consistent in replicated experiments with clonal ß-cells [14]
  • Chronic melatonin administration
    • Ameliorates hyperinsulinemia in vivo [14] !!!
  • 4 mg of melatonin at bedtime for 3 months
    • 23 non-diabetic people with the MTNR1B risk gene variant
    • 22 people without

Leptin

  • Secreted by adipocytes
  • Influence insulin action in fat and liver cells
  • Inhibitory effect on insulin secretion
  • Deficiencies are associated with hyperinsulinemia [14]
  • Antagonizing the action of elevated intracellular cAMP
  • Inhibit insulin secretion by activating PDE 3B, a subtype of PDE [14]
  • Potently inhibits glucoincretin
    • GLP-1-induced insulin secretion [14]
  • Exposure of the embryonic mouse brain to leptin during a key developmental period
    • Permanent alternations in the growth of neurons from the brain stem to the pancreas
      • Long-term disturbances to the balance of insulin levels in the adult mouse [26]
  • Leptin receptors
    • Highly expressed in the brain stem
    • Injected a single dose of leptin directly into the brain of mouse embryos during mid-gestation
      • Permanent effect of reducing connectivity between brain stem and pancreas [26]
        • Impaired glucose regulation in the adult mouse [26]
  • Because babies of obese moms have high levels of leptin
    • Higher risk for type 2 diabetes and obesity [26]

Growth hormone (GH)

  • Stimulate production of IGF-I and its binding proteins [14]
  • Decreases serum levels of insulin and C-peptide in human [14]
    • Directly suppresses insulin secretion [14]
  • V.s. via activation of PDE3B
    • Breaking down cAMP in ß-cells [14]

Stresové hormony

Parasympaticus

  • When the pupil contracted on exposure to light
    • Stimulation of the parasympathetic
      • The animals' blood glucose plummeted [23]

Sympaticus

  • When the pupil dilated in darkness
    • Activated the sympathetic nervous system
      • Blood glucose levels rose [54]

Citlivost na stresové hormony

  • Common gene variant in the population makes insulin-producing cells sensitive to stress hormones
    • Greatly impairs the cells' capacity to secrete insulin [23]
  • 30 % of the population have it [23]
    • Even more frequent among patients with DM2
      • Ze 400 000 DM2 in Sweden až 40 % [23]

Yohimbin

  • Deregistered for several years
  • Effectively blocked the gene variant's damaging effects
    • In animal experiments
    • In insulin-producing cells
  • The capacity to secrete insulin improved
    • Neutralised the effects of the risk gene
      • Yunzhao Tang [23]
  • Must be modified to minimise side-effects
    • Raised blood pressure [23]
  • Drug should be effective in 40 % of DM2
    • Carriers of the genetic risk variant [23]

Spánková apnoe - OSA

  • Compared with control subjects, after ingestion of glucose load.
  • 27 % mužů s OSA - lower insulin sensitivity (estimated by Matsuda index)
  • 37 % mužů s OSA - higher total insulin secretion
  • Presence of OSA u mladých štíhlých mužů is associated with:

Genetika a sekrece inzulínu

  • T.č. známo min. 14 genů, jejichž defekt způsobuje monogenní formu diabetes mellitus
    • Jak beta-buňka rozpoznává glykémii
    • Jak řídí syntézu inzulinu
    • Jak reguluje jeho výdej do krevního oběhu.
    • Jakým způsobem je chráněna před poškozením
      • Vlastním imunitním systémem [7]
      • Dalšími vlivy
  • Epigenetické vlivy a genetika selekcí:
    • Inadequate food
    • Unplanned exercise (escaping predators)
  • Hypoglycemia was more likely than hyperglycemia
    • A single means of lowering blood glucose is advantageous = less chance of inadvertent hypoglycemia
    • Presence of numerous feedback systems to bolster blood sugar is beneficial
  • Selektivní výhoda kdysi = T2D is an increasing problem in societies today [17]
  • Environmental and epigenetic factors
    • Play a large role in disease development in patients with genetic predisposition to the disease [14]

Genome-wide association studies (GWAS)

  • Sequencing of the human genome
  • At least 44 candidate gene loci identified that show significant associations with T2D [14], more than 70 loci [17]
    • Pancreatic beta cell function
      • Alterations in insulin synthesis and secretion are central to the development of the disease

The KCNJ11

  • Potassium inwardly-rectifying channel, subfamily J, member 11
  • Common variant
  • Identified in 2003
  • Encodes a zinc transporter restricted to beta cells
  • Target of sulphonylureas
    • Drugs that bind ATP-dependent potassium channels on beta cells
    • Leading to depolarization and insulin secretion [14]

TCF7L2

  • Associated with reduced insulin secretion
  • Transcription factor 7-like [14]

SLC30A8

  • Solute carrier family 30
  • Zinc transporter, member 8 [14]

CDKAL1

  • CDK5 regulatory subunit associated protein 1-like 1 [14]

alpha-2A-adrenergic receptor mutation

  • Gene variant only explains a small degree of DM2 risk
  • Treatment with a drug targeted to this receptor restored insulin secretion
    • Genotype-specific therapy in T2D
    • Personalized treatments for groups of individuals with specific subtypes of T2D [17]

DNA methylations in four specific genes

  • Predict who is at risk of developing type 2 diabetes
  • Long before the disease occurs
  • Methylations control gene activity [25]
  • The Finnish participants - higher levels of DNA methylation in their first sample
    • Lower risk of DM2 ten years later
    • Cca 1/3 of the Finnish participants had developed DM2 [25]
  • Danish participants - higher DNA methylation in their first sample
    • Higher insulin secretion ten years later [25]
  • ß-cells from T2D patients show altered DNA methylation
    • A common epigenetic mark
    • Changes in gene expression profiles [17]

Maternal and early-life nutrition

Influence the risk of T2D in offspring [17]

Maternal diet low in protein

  • Predisposes offspring to DM2
  • Female mice throughout their pregnancies
    • Normal diet
    • Low in protein
      • Decreased insulin levels
      • Fewer ß cells [24]

Solid foods before a baby is 4-6 months

  • Should not be given [50]
    • Jinak je vyšší riziko obezity a diabetu 2

Prozánětlivé cytokiny

IL-1ß

  • Prolonged exposure associated with reduced insulin secretion
  • Short-term exposure increase insulin levels
    • Amplifies insulin secretion in healthy human islets [25]
  • Reducing IL-1 signaling in DM2
    • Mixed success in clinical studies
      • Multiple effects of IL-1ß in insulin secretion [25]
  • Islets from obese individuals
    • Particularly sensitive to IL-1ß stimulation [25]
  • Islets from obese subjects with DM2
    • Not responsive to IL-1ß [25]
  • In mice
    • Inhibition of IL-1 signaling resulted in symptoms of DM2
      • Glucose intolerance
      • Impaired insulin secretion in response to metabolic stress [25]
  • Directly promotes insulin secretion
    • Enhancing release of insulin-containing granules [25]

Mikrotubuly

  • Glucose destabilizes microtubules just inside the cell surface
    • Release the microtubule hold on insulin granules
      • Allow secretion [29]
  • Microtubules negatively regulate insulin secretion [29]
  • Destroyed microtubules in mice increased:
    • Glucose-stimulated insulin secretion
    • Glucose clearance from the blood [29]
  • Microtubule meshwork
    • Was more dense in beta cells from mice with diabetes [29]
    • Less dynamic as a feedback mechanism [29]
    • Ultimately shutting down beta cell function [29]
  • Anti-cancer therapies that stabilize microtubules
    • Increased risk of diabetes in treated patients
    • May reduce insulin secretion and promote diabetes [29]

Leaky Ca kanál

  • RyR2 channels control intracellular calcium release
  • When leaky - reduce insulin release from the pancreas
    • High blood sugar levels

Rycal

  • Experimental drug that has shown can stop RyR2 leak on CPVT mice with RyR2 mutations and DM2
    • Improved insulin secretion and glucose tolerance in mouse models [38]
  • Ca leaks of RyR2 channels can be stopped with Rycal
    • Glucose levels normalized [38]
  • Rycals are currently being tested in patients with
    • Heart disease
    • Muscle disorders
    • Have a good safety record so far [38]

Kisspeptin 1 ( K1—up)

  • Regulation of puberty and fertility
  • Slows down the production of insulin [42]
  • Liver, stimulated by high levels of glucagon, releases K1 into the bloodstream
    • Homes in on pancreatic beta cells
      • Suppresses insulin secretion [42]
  • Increased in blood and liver samples obtained from people with DM2
    • Appears to be the very cause of the declining insulin secretion seen in DM2 [43]
  • Engineered mice beta cells with no receptors for K1
    • insulin-secreting cells immune to the effects of K1 [43]
      • I během lačnění, na tukové dietě [43]
  • Exposed mouse pancreatic cells to K1-rich blood plasma obtained from people with DM2
    • The insulin production of these cells dropped [42]
  • Offers a possible new treatment target [42]

Životní prostředí

  • About 50 known polymorphisms when combined with harsh environmental factors increase risk of developing the DM2 [34]

Arsen

  • People who drink this water are more susceptible to developing diabetes
    • arsenic modifies the enzyme calpain 10
      • Alters insulin secretion by the pancreas [34]
  • Also influences in the development of skin and bladder cancer [34]
  • Can be present in ground water
  • Mining and overexploitation of underground aquifers are the main factors that contaminate water [34]
    • Contaminates the tap water of northern Mexican states
      • Coahuila
      • Sonora
      • Chihuahua
      • Hidalgo

Pokles metabolické aktivity Krebsova cyklu beta buněk

  • Impaired activation of mitochondrial energy metabolism in the presence of glucose
    • In pancreatic beta-cells from patients with DM2
    • mitochondrial energy metabolism did not harbor a substantial defect
    • Subtle disharmony between bioenergetic supply and demand pathways dampened the response to glucose in the observed individuals [35]

Dioxin

  • Can impair or increase insulin secretion [59]





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Poslední aktualizace: 30. 5. 2016 1:04:37