Basal insulin analogues in people with diabetes and chronic kidney disease.

BACKGROUND: Diabetic kidney disease is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. ESKD has a high prevalence in patients with diabetes mellitus (DM). CKD increases the chances of hypoglycaemia by different mechanisms, causes insulin resistance and a decrease in insulin metabolism. Both the "Kidney Disease: Improving Global Outcomes" (KDIGO) and "American Diabetes Association" (ADA) guidelines recommend the use of insulin as part of treatment, but the type of basal insulin is not specified. METHODS: We reviewed the literature to determine whether first- and second-generation basal insulins are effective and safe in CKD patients. We reviewed specific pivotal studies conducted by pharmaceutical laboratories, as well as independent studies. CONCLUSIONS: Basal insulins are safe and effective in patients with CKD and diabetes mellitus but we do not have specific studies. Given that CKD is one of the main complications of type 2 DM, and insulin specific treatment in the final stages, the absence of studies is striking. Real-life data are also important since trials such as pivotal studies do not fully represent actual patients. Treatment should be individualized until we have specific trials in this type of population.

The gut microbial metabolite imidazole propionate inhibits metformin action.

Imidazole propionate inhibits metformin action in a manner dependent on a p38γ-Akt-AMPK axis.

Phytochemicals against anti-diabetic complications: targeting the advanced glycation end product signaling pathway.

The role of advanced glycation end products (AGEs) is not limited to diabetes and diabetes-related complications. There are multiple modulators, including the receptor for advanced glycation end products, high mobility group box 1, glyoxalase 1, nuclear factor-kappa B, tumor necrosis factor-α, chronic unpredictable stress, reactive oxygen species, and inflammatory cytokines, which interact with AGE signaling and control diabetes, modulating these interacting modulators. The progression of diabetes, as well as related complications, can be controlled and treated. Natural products rich in bioactive constituents can interact with AGEs and their related mediators through various signaling cascades, thereby controlling and preventing the progression of diabetes. This review provides a deeper assessment of the signaling pathway, interactions between phytochemicals and AGEs, and its mediators, to develop a multifold therapeutic approach to prevent and treat diabetes and its related complications.

The PI3K/Akt Cascade Is Involved in the Antidiabetic Effect of Compound GSB-214, a Low-Molecular-Weight BDNF Mimetic.

In our previous studies on the streptozotocin model of diabetes we hypothesized that activation of the PI3K/Akt signaling pathway is essential for the realization of the antidiabetic effect of low-molecular-weight NGF and BDNF mimetics. Here we analyze the effect of a specific PI3K/Akt pathway inhibitor (LY 294002) on the antidiabetic effect of the BDNF loop 1 mimetic GSB-214. The experiments on C57BL/6 mice with streptozotocin-induced diabetes showed that GSB-214 attenuated the hyperglycemic effect of streptozotocin and prevented weight loss typical of diabetes, while LY 294002 eliminated these effects of GSB-214. These findings clearly demonstrate the involvement of PI3K/Akt pathway in the implementation of the effects of this low-molecular-weight BDNF mimetic.

Rosiglitazone ameliorates tissue plasminogen activator-induced brain hemorrhage after stroke.

OBJECTIVE: Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator-activated receptor-γ (PPAR-γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti-inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA-induced HT after stroke. METHODS AND RESULTS: We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA-induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA-treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA-treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA-alone-treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down-regulated in microglia of the RSG-treated mice. We further found that the expression of Arg-1 was also upregulated in those tPA and RSG-treated stroke mice and the protection against tPA-induced HT and BBB disruption in these mice were abolished in the presence of PPAR-γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). CONCLUSIONS: RSG treatment protects against BBB damage and ameliorates HT in delayed tPA-treated stroke mice by activating PPAR-γ and favoring microglial polarization toward anti-inflammatory phenotype.

Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment.

Previous studies have reported that the regulatory function of the different c-Jun N-terminal kinases isoforms (JNK1, JNK2, and JNK3) play an essential role in neurological disorders, such as epilepsy and metabolic-cognitive alterations. Accordingly, JNKs have emerged as suitable therapeutic strategies. In fact, it has been demonstrated that some unspecific JNK inhibitors exert antidiabetic and neuroprotective effects, albeit they usually show high toxicity or lack therapeutic value. In this sense, natural specific JNK inhibitors, such as Licochalcone A, are promising candidates. Nonetheless, research on the understanding of the role of each of the JNKs remains mandatory in order to progress on the identification of new selective JNK isoform inhibitors. In the present review, a summary on the current gathered data on the role of JNKs in pathology is presented, as well as a discussion on their potential role in pathologies like epilepsy and metabolic-cognitive injury. Moreover, data on the effects of synthetic small molecule inhibitors that modulate JNK-dependent pathways in the brain and peripheral tissues is reviewed.

Glucagon receptor signaling in metabolic diseases.

Glucagon is a peptide hormone secreted from the pancreatic alpha cells in response to hypoglycemia but in some patients with type 2 diabetes a paradoxical hypersecretion results from the intake of glucose. In rodent, antagonizing the actions of glucagon have been shown to be effective for lowering blood glucose levels and this has recently have been solidified in patients with type 2 diabetes. Although the reported increases of liver enzymes, hyperglucagonemia, and alpha cell hyperplasia resulting from glucagon receptor antagonism may potentially limit the clinical applicability of glucagon receptor antagonists, they may serve as an instrumental toolbox for delineating the physiology of glucagon. Agonizing glucagon receptor signaling may be relevant, in particular when combined with glucagon-like peptide-1 receptor analogues in the perspective of body weight lowering therapy. Here, we will focus on new conceptual aspects of glucagon biology and how this may led to new diagnostics and treatment of metabolic diseases.

Repurposing Lesogaberan to Promote Human Islet Cell Survival and ß-Cell Replication.

The activation of ß-cell's A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs) can promote their survival and replication, and the activation of α-cell GABAA-Rs promotes their conversion into ß-cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptimal for the long-term treatment of diabetes due to their pharmacological properties or potential side-effects on the central nervous system (CNS). Lesogaberan (AZD3355) is a peripherally restricted high-affinity GABAB-R-specific agonist, originally developed for the treatment of gastroesophageal reflux disease (GERD) that appears to be safe for human use. This study tested the hypothesis that lesogaberan could be repurposed to promote human islet cell survival and ß-cell replication. Treatment with lesogaberan significantly enhanced replication of human islet cells in vitro, which was abrogated by a GABAB-R antagonist. Immunohistochemical analysis of human islets that were grafted into immune-deficient mice revealed that oral treatment with lesogaberan promoted human ß-cell replication and islet cell survival in vivo as effectively as GABA (which activates both GABAA-Rs and GABAB-Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation.

Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 1 Diabetes Also Using Insulin Glargine-SORELLA 1 Study.

BACKGROUND: SAR342434 is a biosimilar follow-on of insulin lispro-Humalog®. This study aimed to show similar efficacy, safety, and immunogenicity of SAR342434 (SAR-Lis) versus insulin lispro-Humalog (Ly-Lis) in adult patients with type 1 diabetes (T1DM) treated with multiple daily injections while using basal insulin glargine (Lantus®; GLA-100). MATERIALS AND METHODS: SORELLA-1 was a randomized, open-label phase 3 study (NCT02273180). Patients completing the 6-month main study continued on SAR-Lis or Ly-Lis, as randomized, for a 6-month safety extension. Assessments included change in HbA1c, fasting plasma glucose (FPG), seven-point self-monitored plasma glucose (SMPG) profiles, hypoglycemic events, treatment-emergent adverse events (TEAEs), and anti-insulin antibodies (AIAs). RESULTS: Five hundred seven patients were randomized (SAR-Lis n = 253; Ly-Lis n = 254). Least square (LS) mean (SEM) change in glycosylated hemoglobin (HbA1c) (baseline to week 26; primary endpoint) was similar in both treatment groups (SAR-Lis: -0.42% [0.051]; Ly-Lis: -0.47% [0.050]). Noninferiority at prespecified 0.3% noninferiority margin and inverse noninferiority were demonstrated (LS mean difference of SAR-Lis vs. Ly-Lis: 0.06% [95% confidence interval: -0.084 to 0.197]). At week 52 (end of extension period) versus week 26, a small HbA1c increase was observed in both groups. FPG and seven-point SMPG profile changes, including postprandial glucose excursions, were similar between groups. At week 52, similar changes in mean daily mealtime and basal insulin doses were observed. Hypoglycemia, TEAEs, and AIAs (incidence, prevalence) did not differ between groups. CONCLUSIONS: Results from this controlled study in patients with T1DM also using GLA-100 support similar efficacy and long-term safety (including immunogenicity) of SAR-Lis and Ly-Lis.

Pharmacological PPARγ modulation regulates sebogenesis and inflammation in SZ95 human sebocytes.

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) controls the expression of genes involved in the regulation of lipid and glucose metabolism, cell proliferation/differentiation as well as inflammatory pathways. Pivotal studies in human sebocytes and isolated sebaceous glands have raised the interesting possibility that compounds acting on PPARγ can modulate sebaceous lipids and inflammation and, as such, may be useful in the treatment of acne. To investigate the role of this receptor in the regulation of lipid synthesis, proliferation and inflammation, we used the SZ95 sebaceous gland cell line stimulated with insulin. In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein/lipid synthesis, increased cell growth and proliferation as well as inflammation. As regards lipogenesis, insulin initially stimulated the formation of unsaturated lipids and then the neosynthesis of lipids. The results showed, that the modulation of PPARγ, counteracted the insulin-induced altered lipogenesis, evident through a decrease in gene expression of key enzymes responsible for the synthesis of fatty acids, and through a reduction of lipid species synthesis analyzed by Oil/Nile Red staining and GC-MS. PPARγ modulation also regulated the insulin-induced proliferation, inhibiting the cell cycle progression and p21WAF1/CIP1 (p21) protein reduction. Moreover, the expression of inflammatory cytokines, induced by insulin or lipopolysaccharide (LPS), was down-modulated. In PPARγ-deficient cells or in the presence of GW9662 antagonist, all these observed effects were abolished, indicating that PPARγ activation plays a role in regulating alteration of lipogenesis, cell proliferation and inflammatory signaling. We demonstrated that selective modulation of PPARγ activity is likely to represent a therapeutic strategy for the treatment of acne.

Implicaciones hemodinámicas y renales de los inhibidores del cotransportador sodio-glucosa tipo 2 en el contexto de la diabetes mellitus tipo 2 / Hemodynamic and renal implications of sodium-glucose cotransporter-2 inhibitors in type 2 diabetes mellitus

Durante la diabetes mellitus tipo 2 se produce un aumento en la expresión del transportador proximal de glucosa SGLT2. Este aumento indebido de la recuperación de glucosa filtrada desde la orina hacia el túbulo proximal y, posteriormente, hacia el torrente sanguíneo tiene 3 repercusiones directas sobre el pronóstico del paciente con diabetes mellitus tipo 2: a) aumento de la carga diaria de glucosa al elevar el umbral de reabsorción. Como consecuencia aumentan los requerimientos de antidiabéticos orales y de insulina. Este aumento es progresivo a lo largo de la enfermedad y va a la par con el aumento de masa renal (hipertrofia renal); b) la mayor reabsorción de glucosa hace que la glucosuria sea menor de la correspondiente al valor de glucemia, disminuyendo el estímulo sobre el «feed-back» tubuloglomerular de la nefrona distal. Como resultado, no se contrarresta la vasodilatación glomerular causada por la hiperglucemia, perpetuándose la hiperfiltración glomerular, y c) el exceso de glucosa transportado a la célula del túbulo proximal modifica el estado redox de esta, aumentando la producción local de productos con capacidad glucosilativa y activando la producción local de mediadores proliferativos proinflamatorios y profibróticos. Estos mediadores son responsables del daño directo por radicales libres a la célula tubular proximal, del aumento de expresión de SGLT2, del aumento de producción de colágeno IV y de matriz extracelular, y de la activación de monocitosmacrófagos con capacidad lesiva endotelial. La utilización de inhibidores del transporte proximal de glucosa SGLT2 no solo reduce la reinyección de la glucosa ya filtrada desde la orina hacia la sangre, mejorando el control metabólico de la diabetes, sino que además restaura el «feed-back» tubuloglomerular al aumentar la glucosuria y el flujo urinario distal. Pero el efecto más notable se debe a la inhibición de la entrada de glucosa en la célula tubular proximal. La glucosuria es tóxica para el riñón: lo es para las células capaces de transportar glucosa, es decir, las células proximales dotadas de SGLT2. En modelos animales, al inhibir SGLT2 se reduce la producción local de radicales de oxígeno, disminuye la formación de matriz mesangial y de colágeno IV, hay menor infiltración glomerular por células inflamatorias y se reduce la arteriosclerosis dependiente de monocito-macrófago. En clínica humana, los iSGLT2 han mostrado su capacidad para reducir el daño renal y el riesgo cardiovascular de los pacientes con diabetes mellitus tipo 2 (AU)

In DM2, there is increased expression of the proximal glucose transporter SGLT2. The increased glucose reabsorption from the urine to the proximal tubule and subsequently to the bloodstream, has three direct effects on the prognosis of patients with DM2: a) it increases the daily glucose load by raising the renal threshold for glucose, thus augmenting requirements for oral antidiabetics and insulin. This progressive increase occurs throughout the course of the disease and in parallel with the increase in renal mass (renal hypertrophy); b) because of the greater glucose reabsorption, glycosuria is lower than the level corresponding to glycaemia, decreasing the stimulus on the tubuloglomerular feedback system of the distal nephron. As a result, the glomerular vasodilation caused by hyperglycaemia is not arrested, maintaining glomerular hyperfiltration, and c) the excess glucose transported to the proximal tubular cells modifies their redox status, increasing local production of glycosylating products and activating local production of proinflammatory and profibrotic proliferative mediators. These mediators are responsible for the direct free radical damage to proximal tubular cells, for increased SGLT2 expression, increased production of collagen IV and extracellular matrix, and activation of monocyte/macrophages able to cause endothelial injury. The use of SGLT2 inhibitors not only reduces the reabsorption of glucose from the glomerular filtrate back into the circulationthus improving metabolic control in diabetesbut also restores tubuloglomerular feedback by increasing glycosuria and distal urinary flow. However, the most notable effect is due to inhibition of glucose entry to the proximal tubular cells. Glycosuria is toxic to the kidney: it harms glucosetransporting cells, that is, the proximal cells, which contain SGLT2. In animal models, SGLT2 inhibition reduces local production of oxygen-free radicals, the formation of mesangial matrix and collagen IV, glomerular infiltration by inflammatory cells and monocyte/macrophage-dependent arteriosclerosis. In humans, SGLT2 have a demonstrated ability to reduce renal injury and cardiovascular risk in patients with type 2 diabetes mellitus (AU)

Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men.

AIMS: To determine the acute effect of glucagon-like peptide-1 (GLP-1) receptor agonist exenatide and the involvement of nitric oxide (NO) on renal haemodynamics and tubular function, in healthy overweight men. METHODS: Renal haemodynamics and tubular electrolyte handling were measured in 10 healthy overweight men (aged 20-27 years; BMI 26-31 kg/m(2)) during intravenous administration of placebo (saline 0.9%), exenatide, and exenatide combined with the NO-synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance techniques, respectively, based on timed urine sampling. Glomerular hydrostatic pressure and vascular resistance of afferent and efferent renal arterioles were calculated using the Gomez formulae. Urinary electrolytes, osmolality and pH were also measured. RESULTS: GFR increased by a mean of 18 ± 20 (+20%; p = 0.021) and ERPF increased by a median (interquartile range) of 68 (26; 197) ml/min/1.73 m(2) (+14%; p = 0.015) during exenatide infusion versus placebo. During L-NMMA infusion, exenatide increased GFR by mean 8 ± 12 ml/min/1.73 m(2) (+9%; p = 0.049). Exenatide increased estimated glomerular pressure by +6% (p = 0.015) and reduced afferent renal vascular resistance by -33% (p = 0.038), whereas these effects were blunted during L-NMMA infusion. Exenatide increased absolute and fractional sodium excretion, urinary osmolality and urinary pH. The tubular effects of exenatide were not altered by concomitant L-NMMA infusion. CONCLUSIONS: Exenatide infusion in healthy overweight men acutely increases GFR, ERPF and glomerular pressure, probably by reducing afferent renal vascular resistance, and at least partially in an NO-dependent manner. As baseline renal haemodynamics in patients with type 2 diabetes differ from those in healthy individuals, clinical studies on the renal effects of GLP-1 receptor agonists are warranted.

Sildenafil does not enhance but rather attenuates vasorelaxant effects of antidiabetic agents.

Type 2 diabetic men commonly experience erectile dysfunction for which phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) are often recommended. By preventing degradation of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle, these inhibitors also enhance arterial vasorelaxant effects of nitric oxide donors (which stimulate cGMP synthesis). In the present work, we confirmed this enhancing effect after co-administration of sildenafil with nitroprusside to freshly-isolated rat tail arterial tissues. However, in the same tissues we also observed that sildenafil does not enhance but rather attenuates vasorelaxant effects of three commonly-used antidiabetic drugs, i.e. the biguanide metformin and the thiazolidinediones pioglitazone and rosiglitazone. Indeed, sildenafil completely blocked vasorelaxant effects of low concentrations of these drugs. In addition, we found that this same novel anti-vasorelaxant interaction of sildenafil with these agents was abolished by either 1) omitting extracellular glucose or 2) inhibiting specific smooth muscle glycolytic pathways; pathways known to preferentially utilize extracellular glucose to fuel certain adenosine triphosphate (ATP)-dependent ion transporters: e.g. ATP-sensitive K channels, sarcoplasmic reticulum Ca-ATPase, plasma membrane Ca-ATPase and Na/K-ATPase. Accordingly, we suspect that altered activity of one or more of these ion transporters mediates the observed attenuating (anti-vasorelaxant) interaction of sildenafil with the antidiabetic drugs. The present results are relevant because hypertension is so common and difficult to control in Type 2 diabetes. The present data suggest that sildenafil might interfere with the known antihypertensive potential of metformin and the thiazolidinediones. However, they do not suggest that it will interact with them to cause life-threatening episodes of severe hypotension, as can occur when it is co-administered with nitrates.

Protocatechuic acid activates key components of insulin signaling pathway mimicking insulin activity.

SCOPE: Insulin resistance represents an independent risk factor for metabolic and cardiovascular diseases. Researchers have been interested in identifying active harmless compounds, as many insulin-sensitizing drugs have shown unwanted side-effects. It has been demonstrated that anthocyanins and one of their representative metabolites, protocatechuic acid (PCA), ameliorate hyperglycemia, and insulin sensitivity. This study investigated the mechanism of action of PCA responsible for the glucose uptake upregulation. METHODS AND RESULTS: In human visceral adipocytes, PCA stimulated insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (+40% with respect to untreated cells) and the downstream events, i.e. phosphoinositide 3-kinase binding to IRS-1 and Akt phosphorylation (+100%, +180%, respectively, with respect to untreated cells). The insulin-like activity of PCA seemed to be mediated by insulin receptor since by inhibiting its autophosphorylation, the PCA effects were completely abolished. Furthermore, PCA was able to activate adenosine monophosphate-activated protein kinase, a serine/threonine kinase whose activation elicits insulin-sensitizing effects. CONCLUSION: This study showed that PCA stimulates the insulin signaling pathway in human adipocytes increasing GLUT4 translocation and glucose uptake. Decreasing insulin resistance is a most desirable aim to be reached for an effective therapeutic/preventive action against metabolic syndrome and type 2 diabetes. Identifying specific food/food components able to improve glucose metabolism can offer an attractive, novel, and economical strategy.

Empagliflozin for the treatment of type 2 diabetes.

INTRODUCTION: Despite the availability of numerous anti-diabetes drugs and treatment guidelines, many patients with type 2 diabetes mellitus (T2DM) do not reach recommended targets for glycemic control. There remains an unmet need for effective and well-tolerated anti-diabetes agents that can be used as monotherapy or in combination with other therapies to improve glycemic control in patients with T2DM. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of treatment for T2DM that reduce hyperglycemia by reducing renal glucose reabsorption and thereby increasing urinary glucose excretion. AREAS COVERED: This paper reviews the pharmacokinetic and pharmacodynamic properties of the SGLT2 inhibitor empagliflozin , the results of clinical trials investigating the efficacy of empagliflozin given as monotherapy or as add-on therapy on glycemic control, body weight, and blood pressure in patients with T2DM, and the safety and tolerability profile of empagliflozin. EXPERT OPINION: Empagliflozin offers good glycemic efficacy, weight loss, blood pressure reduction, and a low risk of hypoglycemia. These attributes, coupled with the ability to be used in virtually any combination with other anti-diabetes agents and at any stage in the disease process, provide a welcome new agent to our armamentarium of drugs to help manage T2DM.

Ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells via bile acid receptor activation.

Compound K (CK) is a major metabolite of ginsenosides that is absorbed. CK has antidiabetic effects, although the mechanisms underlying the effects of CK have not fully been known. To elucidate the mechanisms underlying the antidiabetic effects of CK, we studied the effects of CK on GLP-1 secretion from NCI-H716 cells, and explored the mechanisms underlying CK-induced GLP-1 secretion. Treatment of NCI-H716 cells with 10, 50, and 100 µM CK significantly increased GLP-1 secretion, and intracellular Ca²âº and cAMP levels in a dose-dependent manner. Transfection of NCI-H716 cells with siRNA specific to α-gustducin and siRNA specific to TAS1R3 had no effect on CK-induced GLP-1 secretion and Ca²âº increase. However, transfection of NCI-H716 cells with TGR5-specific siRNA significantly inhibited CK-induced GLP-1 secretion and the increase in Ca²âº and cAMP levels. Moreover, CK showed human TGR5 agonist activity in CHO-K1 cells transiently transfected with human TGR5. Our data provide a novel mechanism of CK for antidiabetic effects. Moreover, the findings might suggest that CK is a potential agent that has multiple biological functions in the body via GLP-1 secretion and TGR5 activation.

Metformin inhibits vascular calcification in female rat aortic smooth muscle cells via the AMPK-eNOS-NO pathway.

Metformin exhibits diverse protective effects against diabetic complications, such as bone loss. Here, we investigated the effect of metformin on vascular calcification, another type 2 diabetes complication. In female rat aortic smooth muscle cells (RASMCs), we observed that metformin significantly alleviated ß-glycerophosphate-induced Ca deposition and alkaline phosphatase activity, corresponding with reduced expression of some specific genes in osteoblast-like cells, including Runx2 and bone morphogenetic protein-2, and positive effects on α-actin expression, a specific marker of smooth muscle cells. Mechanistic analysis showed that phosphorylation levels of both AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) were increased with NO overproduction. After inhibition of either AMPK or eNOS with the pharmacologic inhibitors, compound C or Nω-Nitro-L-arginine methyl ester, NO production was lowered and metformin-meditated vascular protection against ß-glycerophosphate-induced Ca deposition was removed. Our results support that metformin prevents vascular calcification via AMPK-eNOS-NO pathway.

Hemin therapy suppresses inflammation and retroperitoneal adipocyte hypertrophy to improve glucose metabolism in obese rats co-morbid with insulin-resistant type-2 diabetes.

AIM: Visceral adiposity and impaired glucose metabolism are common patho-physiological features in patients co-morbid with obesity and type-2 diabetes. We investigated the effects of the heme-oxygenase (HO) inducer hemin and the HO blocker stannous-mesoporphyrin (SnMP) on glucose metabolism, adipocyte hypertrophy and pro-inflammatory cytokines/mediators in Zucker diabetic fatty (ZDF) rats, a model characterized by obesity and type-2 diabetes. METHODS: Histological, morphological/morphometrical, Western immunoblotting, enzyme immunoassay, ELISA and spectrophotometric analysis were used. RESULTS: Treatment with hemin enhanced HO-1, HO activity and cGMP, but suppressed retroperitoneal adiposity and abated the elevated levels of macrophage-chemoattractant protein-1 (MCP-1), ICAM-1, tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-1ß, NF-κB, c-Jun-NH2-terminal-kinase (JNK) and activating-protein (AP-1), with parallel reduction of adipocyte hypertrophy. Correspondingly, important proteins of lipid metabolism and insulin-signalling such as lipoprotein lipase (LPL), insulin-receptor substrate-1 (IRS-1), GLUT4, PKB/Akt, adiponectin, the insulin-sensitizing and anti-inflammatory protein and adenosine-monophosphate-activated protein kinase (AMPK) were significantly enhanced in hemin-treated ZDF rats. CONCLUSION: Elevated retroperitoneal adiposity and the high levels of MCP-1, ICAM-1, TNF-α, IL-6, IL-1ß, NF-κB, JNK and AP-1 in untreated ZDF are patho-physiological factors that exacerbate inflammatory insults, aggravate adipocyte hypertrophy, with corresponding reduction of adiponectin and deregulation of insulin-signalling and lipid metabolism. Therefore, the suppression of MCP-1, ICAM-1, TNF-α, IL-6, IL-1ß, NF-κB, JNK, AP-1 and adipocyte hypertrophy, with the associated enhancement of LPL, adiponectin, AMPK, IRS-1, GLUT4, PKB/Akt and cGMP in hemin-treated ZDF are among the multifaceted mechanisms by which the HO system combats inflammation to potentiate insulin signalling and improve glucose and lipid metabolism. Thus, HO inducers may be explored in the search of novel remedies against the co-morbidities of obesity, dysfunctional lipid metabolism and impaired glucose metabolism.

Oral administration of corn zein hydrolysate stimulates GLP-1 and GIP secretion and improves glucose tolerance in male normal rats and Goto-Kakizaki rats.

We have previously demonstrated that ileal administration of the dietary protein hydrolysate prepared from corn zein (ZeinH) stimulated glucagon-like peptide-1 (GLP-1) secretion and attenuated hyperglycemia in rats. In this study, to examine whether oral administration of ZeinH improves glucose tolerance by stimulating GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion, glucose tolerance tests were performed in normal Sprague-Dawley male rats and diabetic Goto-Kakizaki (GK) male rats. The test solution was gavaged before ip glucose injection in normal rats or gavaged together with glucose in GK rats. Blood samples were collected from the tail vein or by using the jugular catheter to measure glucose, insulin, GLP-1, and GIP levels. In the ip glucose tolerance test, oral administration of ZeinH (2 g/kg) significantly suppressed the glycemic response accompanied by an immediate increase in plasma GLP-1 and GIP levels in normal rats. In contrast, oral administration of another dietary peptide, meat hydrolysate, did not elicit a similar effect. The glucose-lowering effect of ZeinH was attenuated by a GLP-1 receptor antagonist or by a GIP receptor antagonist. Furthermore, oral ZeinH induced GLP-1 secretion and reduced glycemic response in GK rats under the oral glucose tolerance test. These results indicate that the oral administration of the dietary peptide ZeinH improves glucose tolerance in normal and diabetic rats by its incretin-releasing activity, namely, the incretinotropic effect.

L-Carnitine for the treatment of a calcium channel blocker and metformin poisoning.

INTRODUCTION: The object of the current communication is to discuss the theory and the evidence for the use of L-carnitine in calcium channel blocker and metformin poisonings. CASE REPORT: A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of L-carnitine was administered as a last resort. One hour after L-carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days. DISCUSSION: L-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning.