Control of the blood sugar of Metformin begins in the brain, not only in the liver, discovers the study

Scientists discover how low -target metformin the brain roads to lower blood sugar, opening fresh ways for safer and more intelligent therapies of diabetes.

Study: Metformin at low doses requires a brain rap1 for its anti -diabetic action. In addition, Image credit: Kateryna Kon / Shutterstock

In a recent study published in the journal Scientific advancesThe researchers have tested if the low. For example, clinically relevant doses of metformin lower the blood sugar level of protein 1 linked to RAS (RAP1) in the Ventromedial Hypothalamic (VMH) nucleus of the brain.

Classic models place the action of metformin in the liver control blood sugar metformin begins through the kinase protein activated by adenosine 5′-monophosphate (AMPK). Moreover, but more recent works add the signaling of adenosine 3 ‘, cyclic monophosphate (camp), mitochondrial targets and effects mediated by glucagon-1 (GDF1) GDF1). Consequently, The central nervous system closely regulates glucose through hypothalamic circuits. Furthermore, so even small drug signals in the brain can move the metabolism of the whole body.

It remains an uncertainty as to the relative importance of these paths in doses of clinically relevant metformin. Similarly, Could the low doses of metformin operate by a neuronal route? Moreover, This study addresses this question and highlights the need to continue research to dissect the brainways to the organ.

The researchers used mice to test a brain -based lane. Furthermore, They compared the normal litter companions with the RAP1δCNS mice. In addition, a specific RAP1 KNOCKOUT from the anterior brain generated by removing RAP1A and RAP1B in neurons control blood sugar metformin begins expressing calcium / calmodulin. Similarly, All mice have received a speed -rich diet to increase blood sugar (hyperglycemia). Similarly, They have received simple. Furthermore, repeated intraperitoneal doses of anti-diabetic agents such as metformin (a beef), rosiglitazone (a thiazolidinedione), the exendine-4 (an agonist of the GLP-1 receiver), the glibenclamide (a sulfonylurated), the dapagliflozine (a inhibitor SGLT2) and the insult. However, The dose-answer tests used metformin at 50–150 mg / kg. However, glucose tolerance tests (GTTS) with an area in the curve analysis (AUC).

To probe the central action. metformin has been issued by intracerebroventricular injection (ICV) (1–30 μg) to the obese mice induced by the diet, with food inspections and body weight monitoring. Electrophysiology in hypothalamic slices assessed how metformin modifies the firing of steroidogenic factor 1 (SF1) in VMH. Function gain experiences expressed a constitutively active RAP1 (RAP1V12) using the adeno-associated virus (AAV) in VMH. a Rosa26-Lox-Stop-Lox (LSL) -Rap1v12 × control blood sugar metformin begins Camki_ Croix to raise CNS RAP1 activity. The results included blood sugar, glucose tolerance and C-FOS cartography of neural activation.

The removal of rap1 in the neurons of the anterior brain produced a selective defect in the reactivity of. the metformin. In litter witnesses. metformin has lowered blood sugar, but rap1δCNS mice have not shown a significant reduction in glucose to metformin despite normal responses to other anti -diabetic agents. Thus. the overall capacity of glucose housing was intact, but the effect of metformin was specifically lost when the brain rap1 was absent.

Dose-response studies have sharpened this selectivity. At 50–150 mg / kg. metformin reduced blood sugar in witnesses in a dose-dependent manner (quantified by AUC), but the same doses failed in rap1δCNS mice. GTTS has shown that low -dose metformin improves tolerance in witnesses. while rap1δCNS mouses have won this profit only during suprapharmacological exposure (≥ 200 mg control blood sugar metformin begins / kg), which implies that high concentrations can bypass the brain. This underlines that the brain rap1 requirement is specific to low. clinically relevant doses of Metformin, while the higher and less relevant doses probably act by peripheral mechanisms.

Directly targeting the brain confirmed the sufficiency. Metformin ICV (as low as 1 to 10 μg) lowered acute blood sugar in obese mice induced by food. in models deficit by leptin (OB / OB) and treated with streptozotocin, regardless of food intake and weight loss, indicating a medieval glycemic effect to the administration of minuscules with systemic administration.

C-Fos Mapping of neurons sensitive to metformin located in VMH. Electrophysiology has shown that METFORMINE depolarized VMH SF1 neurons. an increase in fire; This response was largely abolished when RAP1 was removed from SF1 neurons, involving a VMH node dependent on rap1 as a target of metformin.

The genetics of gain and loss control blood sugar metformin begins of function cemented causality. In mice RAP1CNSV12 (Active RAP1 constitutively in the anterior brain). Jewish blood sugar and intolerance were higher, and metformin has no longer improved glucose excursions during GTTS. Similarly. forcing the expression of rap1v12 bilaterally in VMH using AAV blunt both agitated and chronic of the abandonment of glucose by metformin and improvements induced by metformin clearly altered in glucose tolerance. Conversely. the abolition of RAP1 specifically in SF1 neurons lowered blood sugar to the same degree as metformin and eliminated any additional acute or chronic effect of the drug. Together, these manipulations show that the therapeutic effect of metformin requires an inhibition of rap1 in the VMH SF1 neurons.

The pharmacological context is important because the concentrations of the brain. cerebrospinal fluid to the possibility of therapeutic dosage are ~ 0.5 to 10 micromolar, well below hepatic or intestinal levels. In this range. metformin has activated control blood sugar metformin begins SF1 neurons and reduced rap1 activity, in accordance with a very sensitive central mechanism which dominates in low doses, while higher, less clinical doses probably recruit peripheral ways and can bypass the requirement of CNS RAP1. The study does not exclude the possibility of direct effects of metformin on peripheral tissues such as the liver. the intestine at higher doses.

In mice devoid of rap1 neuronal. basic blood sugar is often reduced, which can limit the observable effect of the administration of additional metformin (“floor effect”). However. even in groups with blood sugar, metformin failed to lower glucose in rap1δCNS mice but has remained effective in witnesses.

The study also highlights the potential involvement of other regulators. such as exchange proteins directly activated by MFF 2 (EPAC2), in the activation of RAP1 in the brain, as well as possible connections with the Lysosomal AMPK route. Although this has not been control blood sugar metformin begins directly tested in this study, it represents a promising avenue for future research.

To summarize. this study identifies a brain mechanism for metformin in therapeutic exposure: low doses inhibit rap1 in SF1 VMH neurons to lower blood sugar. The effect is selective for metformin in agents approved by the Food. Drug Administration of the United States and is lost when the SNC RAP1 is deleted or activated in a constitutive manner, but restored in very high and less relevant doses which probably act peripherally. Although the results highlight the importance of the VMH RAP1 track at low. clinically relevant doses, they do not exclude peripheral mechanisms at higher doses or in other contexts. For patients. clinicians, this brain route helps to explain why the modest doses work safely and in a coherent manner, and it points to central rap1 signaling as a target to refine the diabetic therapies that coordinate control blood sugar metformin begins the liver, muscle and intestine.