Defective Allele of the Neuronal Nitric Oxide Synthase Gene Increases Insulin Resistance During Acute Phase of Myocardial Infarction.

BACKGROUND: Glycemic disorders are strong predictors of mortality in ST-elevation myocardial infarction (STEMI) patients, and disruption in nitric oxide (NO) production is associated with insulin-resistant states. We evaluated whether a defective allele of the neuronal nitric oxide synthase (nNOS) gene (NOS1) might influence insulin response and blood-glucose balance during the acute phase of STEMI and if post-infarction total plasma-NO levels and vasodilation scores varied across nNOS genotypes. METHODS: Consecutive patients with STEMI (n=354) underwent clinical evaluations and genotyping for the promoter variation rs41279104. In-hospital clinical and blood evaluations were performed at admission and five days after STEMI, with glycemic, insulinemic, and disposition indices assessed at the same times. Flow-mediated dilation (FMD) was assessed by reactive hyperemia on the 30th day. RESULTS: Homozygotes for the defective allele (A) showed lower glycemia and insulin sensitivity on day 1 while showing the highest ß-cell function and no changes in the circulating NO pool, which is compatible with hyperresponsive ß cells counteracting the inherent glucose-resistant state of AA patients. At day 5, glycemic scores had shifted to indicate greater insulin sensitivity among A homozygotes, paralleled by a significant yet poor increase in NO bioavailability compared to that among G carriers. All in all, defective homozygotes showed greater insulin resistance at admission that had reversed by 5 days after STEMI. Even so, A carriers developed lower FMD scores compared to G homozygotes after the acute phase. CONCLUSION: A defective nNOS allele (and due decline in NO production) seemed to elicit a hyperinsulinemia response to compensate for an insulin-resistant state during the acute phase of STEMI and to be associated with poor endothelial function after the acute phase.

Inhibition of the sodium-glucose co-transporter 2 in the elderly: clinical and mechanistic insights into safety and efficacy.

The prevalence of type 2 diabetes mellitus (T2DM) in the elderly grew sharply over the last decade. Reduced insulin sensitivity and secretory capacity, weight gain, sarcopenia, and elevated adiposity are all common metabolic and body changes in the aging population that favor an increased risk of hypoglycemia, frailty syndrome, falls, and cognitive dysfunction. First line antidiabetic therapy is frequently not safe in older individuals because of its high risk of hypoglycemia and prevalent co-morbid diseases, such as chronic kidney disease, osteoporosis, cardiovascular disease, and obesity. Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a new class of antidiabetic therapy that inhibits glucose and sodium reabsorption on renal proximal convoluted tubule. Its effect is well demonstrated in various clinical scenarios in the younger population. This review and metanalysis describe particularities of the SGLT2i on the elderly, with mechanistic insights of the potential benefit and remaining challenges about the use of these drugs in this important age group. Further, we will present a meta-analysis of the main effects of SGLT2i reported in post-hoc studies in which the median age of the subgroups analyzed was over 60 years. Despite the absence of specific clinical trials for this population, our findings suggest that SGLT2i therapy on older individuals is effective to lower glucose and maintain its effect on systolic blood pressure and body weight.

Inhibition of the sodium-glucose co-transporter 2 in the elderly: clinical and mechanistic insights into safety and efficacy

SUMMARY The prevalence of type 2 diabetes mellitus (T2DM) in the elderly grew sharply over the last decade. Reduced insulin sensitivity and secretory capacity, weight gain, sarcopenia, and elevated adiposity are all common metabolic and body changes in the aging population that favor an increased risk of hypoglycemia, frailty syndrome, falls, and cognitive dysfunction. First line antidiabetic therapy is frequently not safe in older individuals because of its high risk of hypoglycemia and prevalent co-morbid diseases, such as chronic kidney disease, osteoporosis, cardiovascular disease, and obesity. Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a new class of antidiabetic therapy that inhibits glucose and sodium reabsorption on renal proximal convoluted tubule. Its effect is well demonstrated in various clinical scenarios in the younger population. This review and metanalysis describe particularities of the SGLT2i on the elderly, with mechanistic insights of the potential benefit and remaining challenges about the use of these drugs in this important age group. Further, we will present a meta-analysis of the main effects of SGLT2i reported in post-hoc studies in which the median age of the subgroups analyzed was over 60 years. Despite the absence of specific clinical trials for this population, our findings suggest that SGLT2i therapy on older individuals is effective to lower glucose and maintain its effect on systolic blood pressure and body weight.

RESUMO A prevalência da diabetes mellitus tipo 2 em idosos cresceu muito na última década. A redução na sensibilidade à insulina e na capacidade secretora, ganho de peso, sarcopenia e adiposidade elevada são todas alterações metabólicas e corporais comuns entre a população idosa. Essas mudanças críticas favorecem o aumento no risco de hipoglicemia, síndrome de fragilidade, quedas e disfunções cognitivas. A primeira linha de tratamento contra a diabete muitas vezes não é segura para indivíduos mais velhos devido ao alto risco de hipoglicemia e a prevalência de comorbidades patogênicas, como doença renal crônica, osteoporose, doença cardiovascular e obesidade. Os inibidores do cotransportador sódio-glicose 2 (SGLT2) são uma nova classe de tratamento contra a diabete que inibe reabsorção de glicose e sódio na parte convoluta do túbulo proximal. Seu efeito é claramente demonstrado em diversos cenários clínicos em populações mais jovens. Esta revisão e meta-análise descreve as particularidades dos SGLT2 na população idosa, abordando os mecanismos dos potenciais benefícios e desafios ainda presentes do uso destes medicamentos nesse grupo etário tão importante. Além disso, apresentaremos uma meta-análise dos principais efeitos dos SGLT2 encontrados em estudos post-hoc nos quais a idade média dos subgrupos analisados foi acima de 60 anos. Apesar da ausência de ensaios clínicos que incluem essa população, os dados encontrados sugerem que o tratamento com SGLT2 em idosos é eficaz para diminuir os níveis de glicose e tem efeitos na pressão arterial sistólica e no peso corporal.