Rizikové faktory - 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 3,2 mmol/l
- Sekrece kortizolu
- glykémie pod 2,8 mmol/l
- Kognitivní dysfunkce
- glykémie 2,2 mmol/l
- Letargie
- glykémie 1,7 mmol/l
- Kóma
- glykémie 1,1 mmol/l
- Křeče
- 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
- Uvolněné zejména z viscerální tukové tkáně /potravy
- Vstupují do B-buňky / játer a svalu
- Zvýšené množství MK uvnitř buňky + diacylglycerol (DAG)
- Tlumí metabolismus glukózy
- Prohloubí inzulínovou rezistenci [10]
- Molekula DAG (di-acyl-glycerol)
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]
- Mice
- 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
- Nižší hladina inzulínu
- 22 people without
- 3x vyšší hladiny inzulínu [24]
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:
- Insulin resistance
- Compensatory rise in insulin secretion
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]
HERV-W Env expression has been recently studied in type 1 diabetes, showing significant upregulation in 70% of diabetes patients as compared to a 12% positivity in healthy controls (Levet et al., 2017). The immunostaining of the protein in pancreatic specimens from 20 cases and 19 controls gave comparable positivity percentages (75 and 16%, respectively), showing a predominant localization in acinar cells, proximal to Langerhans islets (Levet et al., 2017). Furthermore, mice transgenic for HERV-W Env expression developed hyperglycemia, diminished insulin levels and pancreatic infiltrates of immune cells, all hallmarks of type I diabetes (Levet et al., 2017). In particular, the inhibition of insulin secretion was determined by HERV-W Env protein in a dose-dependent manner, being restored in the presence of neutralizing Abs and possibly depending on the protein interaction with pancreatic ß cell TLR4 (Levet et al., 2017). Hence, authors suggested that HERV-W-Env might exert a double pathological effect, impairing pancreatic ß cell insulin secretion and stimulating autoimmune reactions. It is worth noting that a phase-IIa clinical trial is currently testing GNbAC1 monoclonal Ab as possible HERV-based therapeutic approach in type 1 diabetes (Levet et al., 2017).HERV-Khttps://www.frontiersin.org/articles/10.3389/fmicb.2018.00462/full
