131 research outputs found
Clinical view on the need to develop new anti-diabetic drugs
No full textType 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Type 2 diabetic individuals are also characterized by reduced Î2-cell mass likely due to increased cellular apoptosis. Traditional strategies to treat diabetes have been developed with the main purpose of reducing hyperglycemia, and include insulin sensitizers, α-glucosidase inhibitors, and Î2-cell secretagogues. However, available drugs do not fully correct the phenotypic abnormalities in diabetes (e.g., insulin resistance, insulin deficiency) and have limited tolerability. Additionally, several available therapies are associated with weight gain or enhanced risk of hypoglycemia. Thus, newer approaches are urgently required. Particular emphasis should be placed on developing pharmacological interventions that are dependent on physiological responses and adequately target underlying defects, such as obesity, insulin resistance, increased glucose output from the liver, secretory dysfunction, or apoptosis of the Î2-cell. Individual phenotypic and genetic characterization of the diabetic patients will allow to define more and more personalized and effective algorithms for the treatment of hyperglycemia. © 2005 Bentham Science Publishers Ltd
GLP-1 Receptor Agonist Added to Insulin versus Basal-plus or Basal-bolus Insulin Therapy in Type 2 Diabetes: A Systematic Review and Meta-analysis
No full textAims Current guidelines recommend that anti‐hyperglycemic treatment in patients with type 2 diabetes not achieving the HbA1c target on basal insulin should be intensified with a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) or basal‐plus/basal‐bolus insulin regimen (BP/BB). We conducted a systematic review and meta‐analysis to compare the effects of GLP‐1RA/insulin combinations versus BP/BB. Materials and methods The review was registered on PROSPERO (CRD42017079547). PubMed, Scopus, CENTRAL and Clinicaltrials.gov were searched until July 2018. All RCTs reporting HbA1c, body weight, daily insulin dose, hypoglycemic events and discontinuation due to lack of efficacy were included. A subgroup analysis on different combinations of GLP‐1RA and insulin was performed. Results Out of 1,885 retrieved papers, 13 RCTs were included in the review. Compared to BP/BB, GLP‐1RA/insulin combinations were associated with a similar HbA1c reduction (Δ=‐0.06%; 95%CI ‐0.14 to 0.02; p=0.13; I2=52%), greater weight loss (Δ=‐3.72 kg; 95%CI ‐4.49 to ‐2.95; p<0.001; I2=89%) and lower incidence of hypoglycemic events (RR=0.46; 95%CI 0.38 to 0.55; p<0.001; I2=99%). The daily insulin dose among GLP‐1RA/insulin users was 30.3 IU/day (95%CI ‐41.2 to ‐19.3; p<0.001; I2=94%), lower than with BP/BB. No difference was found for discontinuation due to lack of efficacy. Conclusions The present review supports treatment intensification with GLP‐1RA added to insulin versus BP/BB in uncontrolled type 2 diabetes. This could provide similar anti‐hyperglycemic efficacy while leading to weight loss and sparing of hypoglycemia and insulin dose. As a consequence, a considerable number of patients with type 2 diabetes could be potentially shifted from BP/BB to GLP‐1RA/insulin combinations
Hepatokines, bile acids and ketone bodies are novel Hormones regulating energy homeostasis
No full textCurrent views show that an impaired balance partly explains the fat accumulation leading to obesity. Fetal malnutrition and early exposure to endocrine-disrupting compounds also contribute to obesity and impaired insulin secretion and/or sensitivity. The liver plays a major role in systemic glucose homeostasis through hepatokines secreted by hepatocytes. Hepatokines influence metabolism through autocrine, paracrine, and endocrine signaling and mediate the crosstalk between the liver, non-hepatic target tissues, and the brain. The liver also synthetizes bile acids (BAs) from cholesterol and secretes them into the bile. After food consumption, BAs mediate the digestion and absorption of fat-soluble vitamins and lipids in the duodenum. In recent studies, BAs act not simply as fat emulsifiers but represent endocrine molecules regulating key metabolic pathways. The liver is also the main site of the production of ketone bodies (KBs). In prolonged fasting, the brain utilizes KBs as an alternative to CHO. In the last few years, the ketogenic diet (KD) became a promising dietary intervention. Studies on subjects undergoing KD show that KBs are important mediators of inflammation and oxidative stress. The present review will focus on the role played by hepatokines, BAs, and KBs in obesity, and diabetes prevention and management and analyze the positive effects of BAs, KD, and hepatokine receptor analogs, which might justify their use as new therapeutic approaches for metabolic and aging-related diseases
Insulin signalling in human adipose tissue
No full textAdipose tissue is a critical regulator of energy balance and substrate metabolism, and synthesizes several different substances with endocrine or paracrine functions, which regulate the overall energetic homeostasis. An excessive amount of adipose tissue has been associated with the development of type 2 diabetes, premature atherosclerosis, and cardiovascular disease. It is believed that the adverse metabolic impact of visceral fat relies on a relative resistance to the action of insulin in this depot compared to other adipose tissue depots. However, information on insulin signalling reactions in human fat is limited. In this paper, we review the major insulin signalling pathways in adipocytes and their relevance for metabolic regulation, and discuss recent data indicating different signalling properties of visceral fat as compared to other fat depots, which may explain the metabolic and hormonal specificity of this fat tissue depot in humans. © 2006 Informa UK Ltd
Insulin and Insulin Receptors in Adipose Tissue Development
No full textInsulin is a major endocrine hormone also involved in the regulation of energy and lipid metabolism via the activation of an intracellular signaling cascade involving the insulin receptor (INSR), insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K) and protein kinase B (AKT). Specifically, insulin regulates several aspects of the development and function of adipose tissue and stimulates the differentiation program of adipose cells. Insulin can activate its responses in adipose tissue through two INSR splicing variants: INSR-A, which is predominantly expressed in mesenchymal and less-differentiated cells and mainly linked to cell proliferation, and INSR-B, which is more expressed in terminally differentiated cells and coupled to metabolic effects. Recent findings have revealed that different distributions of INSR and an altered INSR-A:INSR-B ratio may contribute to metabolic abnormalities during the onset of insulin resistance and the progression to type 2 diabetes. In this review, we discuss the role of insulin and the INSR in the development and endocrine activity of adipose tissue and the pharmacological implications for the management of obesity and type 2 diabetes
Computerized video-capillaroscopy alteration related to diabetes mellitus and its complications
No full textDiabetes mellitus (DM)-associated hyperglycemia contributes to the initiation and progression of chronic microvascular (MIC) and macrovascular (MAC) complications. To carry out early identification of MIC, standardized and inexpensive tests are needed. Computerized nailfold video-capillaroscopy (CNVC) is a noninvasive tool to easily evaluate MIC at the level of the fingers and could be useful to detect the so-called ‘diabetic capillaropathy’. Aim: This was a prospective study using CNVC to examine the prevalence of capillaroscopic patterns in a cohort of type 1 (T1D) and type 2 (T2D) diabetic individuals, and to assess their relationship with the level of glycemic control (HbA1c) and DM-related complications. Results: Nailfold alterations were found to be more prevalent in diabetics, including tortuosity (p < 0.01), avascular zones (p < 0.01), ectasiae (p < 0.01) and capillary with bizarre shape (p < 0.01). At least two of these patterns were found with a higher prevalence in T1D and T2D individuals vs. controls (p < 0.01). Finally, a higher frequency of ‘capillary score’ equal to or higher than 2 points was found to be associated with worse glycemic control, and with the presence of diabetic retinopathy. Conclusions: These results confirm the presence of a ‘diabetic capillaropathy’, and nailfold capillary alterations appear to be related to the level of glycemic control and the existence of MIC, particularly when retinal damage is involved
The chronic alcohol consumption influences the gonadal axis in men: Results from a meta-analysis
No full textBackground: Low testosterone concentrations affect 2-13% of adult males, with a direct association between reduction in testosterone (T) concentrations and cardiovascular events. Lifestyle habits have been linked to visceral fat accumulation and endocrine disorders like secondary hypogonadism. Alcohol intake has also been a topic of debate, with studies showing a detrimental effect on sperm production and underlying mechanisms. This meta-analysis aims to comprehensively evaluate the effect of alcohol consumption on T serum concentrations in adult men. Methods: The literature search included only controlled clinical trials comparing men who drink alcohol to men who do not, or who assumed placebo or nonalcoholic beverages. The primary outcome was the comparison of total testosterone serum concentrations between the study and control groups. The publications were examined for publication bias using Egger's test. Results: Twenty-one studies were included in the analysis for a total of 30 trials that examined the effects of alcohol consumption on testosterone level in 10,199 subjects. The meta-analysis showed that alcohol consumption overall is related to significant reduction in circulating concentrations of total testosterone (mean difference [MD] = -4.02; 95% CI -6.30, -1.73), free T (MD = -0.17; 95% CI -0.23, -0.12), sex hormone binding globulin (SHBG) (MD = -1.94; 95% CI -3.37, -0.48), an increase in estradiol (E2) (MD = 7.65; 95% CI 1.06, 14.23) and neutral effect on luteinizing hormone (LH) (MD = -0.15; 95% CI -0.36, 0.06), independently by age, body mass index (BMI), E2, and LH serum concentrations and alcohol intake. However, these results are evident only in healthy men exposed to chronic alcohol consumption and not in those with a recognized diagnosis of alcohol use disorder or after acute alcohol intake. Conclusion: This study suggests how chronic alcohol consumption may inhibit the gonadal axis in healthy men, although the exact pathophysiological mechanisms connecting alcohol exposure and steroidogenesis are still not completely clarified
To beer or not to beer: a meta-analysis of the effects of beer consumption on cardiovascular health.
No full textA moderate alcohol consumption is demonstrated to exert a protective action in terms of cardiovascular risk. Although this property seems not to be beverage-specific, the various composition of alcoholic compounds could mediate peculiar effects in vivo. The aim of this study was to evaluate potential beer-mediated effects on the cardiovascular health in humans, using a meta-analytic approach (trial registration number: CRD42018118387). The literature search, comprising all English articles published until November, 30th 2019 in EMBASE, PubMed and Cochrane database included all controlled clinical trials evaluating the cardiovascular effects of beer assumption compared to alcohol-free beer, water, abstinence or placebo. Both sexes and all beer preparations were considered eligible. Outcome parameters were those entering in the cardiovascular risk charts and those related to endothelial dysfunction. Twenty-six trials were included in the analysis.
Total cholesterol was significantly higher in beer drinkers compared to controls (14 studies, 3.52 mg/dL, 1.71-5.32 mg/dL). Similar increased levels were observed in high-density lipoprotein (HDL) cholesterol (18 studies, 3.63 mg/dL, 2.00-5.26 mg/dL) and in apolipoprotein A1 (5 studies, 0.16 mg/dL, 0.11-0.21 mg/dL), while no differences were detected in low density lipoprotein (LDL) cholesterol (12 studies, -2.85 mg/dL, -5.96-0.26 mg/dL) and triglycerides (14 studies, 0.40 mg/dL, -5.00-5.80 mg/dL) levels. Flow mediated dilation (FMD) resulted significantly higher in beer-consumers compared to controls (4 studies, 0.65%, 0.07-1.23%), while blood pressure and other biochemical markers of inflammation did not differ. In conclusion, the specific beer effect on human cardiovascular health was meta-analysed for the first time, highlighting an improvement of the vascular elasticity, detected by the increase of FMD (after acute intake), and of the lipid profile with a significant increase of HDL and apolipoprotein A1 serum levels. Although the long-term effects of beer consumption are not still understood, a beneficial effect of beer on endothelial function should be supposed
Cardiovascular effects of antiobesity drugs: are the new medicines all the same?
No full textWaiting for a definite answer from well-designed randomized prospective clinical trials, the impact of the new antiobesity drugs -liraglutide, bupropion/naltrexone, phentermine/topiramate and lorcaserin- on cardiovascular outcomes remains uncertain. What has been learned from previous experience with older medicines is that antiobesity drugs may influence cardiovascular health not only causing weight reduction but also through direct actions on the cardiovascular system. Therefore, in the present review, we examine what is known, mainly from preclinical investigations, about the cardiovascular pharmacology of the new antiobesity medicines with the aim of highlighting potential mechanistic differences. We will show that the two active substances of the bupropion/naltrexone combination both exert beneficial and unwanted cardiovascular effects. Indeed, bupropion exerts anti-inflammatory effects but at the same time it does increase heart rate and blood pressure by potentiating catecholaminergic neurotransmission, whereas naltrexone reduces TLR4-dependent inflammation and has potential protective effects in stroke but also impairs cardiac adaption to ischemia and the beneficial opioid protective effects mediated in the endothelium. On the contrary, with the only exception of a small increase in heat rate, liraglutide only exerts favorable cardiovascular effects by protecting myocardium and brain from ischemic damage, improving heart contractility, lowering blood pressure and reducing atherogenesis. As far as the phentermine/topiramate combination is concerned, no direct cardiovascular beneficial effect is expected for phentermine (as this drug is an amphetamine derivative), whereas topiramate may exert cardioprotective and neuroprotective effects in ischemia and anti-inflammatory and antiatherogenic actions. Finally, lorcaserin, a selective 5HT2C receptor agonist, does not seem to exert significant direct effects on the cardiovascular system though at very high concentrations this drug may also interact with other serotonin receptor subtypes and exert unwanted cardiovascular effects. In conclusion, the final effect of the new antiobesity drugs on cardiovascular outcomes will be a balance between possible (but still unproved) beneficial effects of weight loss and "mixed" weight-independent drug-specific effects. Therefore comparative studies will be required to establish which one of the new medicines is more appropriate in patients with specific cardiovascular diseases
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