Inhibition of renal glucose reabsorption as a novel treatment for diabetes patients.

UNLABELLED: The importance of the kidney in glucose homeostasis has been recognized for many years. Recent observations indicating a greater role of renal glucose metabolism in various physiologic and pathologic conditions have rekindled the interest in renal glucose handling as a potential target for the treatment of diabetes. The enormous capacity of the proximal tubular cells to reabsorb the filtered glucose load entirely, utilizing the sodium-glucose co-transporter system (primarily SGLT-2), became the focus of attention. Original studies conducted in experimental animals with the nonspecific SGLT inhibitor phlorizin showed that hyperglycemia after pancreatectomy decreased as a result of forced glycosuria. Subsequently, several compounds with more selective SGLT-2 inhibition properties ("second-generation") were developed. Some agents made it into pre-clinical and clinical trials and a few have already been approved for commercial use in the treatment of type 2 diabetes. In general, a 6-month period of therapy with SGLT-2 inhibitors is followed by a mean urinary glucose excretion rate of ~80 g/day accompanied by a decline in fasting and postprandial glucose with average decreases in HgA1C ~1.0%. Concomitant body weight loss and a mild but consistent drop in blood pressure also have been reported. In contrast, transient polyuria, thirst with dehydration and occasional hypotension have been described early in the treatment. In addition, a significant increase in the occurrence of uro-genital infections, particularly in women has been documented with the use of SGLT-2 inhibitors. CONCLUSION: Although long-term cardiovascular, renal and bone/mineral effects are unknown SGLT-2 inhibitors, if used with caution and in the proper patient provide a unique insulin-independent therapeutic option in the management of obese type 2 diabetes patients.

Inhibition of renal glucose reabsorption as a novel treatment for diabetes patients / Inibicao da reabsorcao renal de glicose como uma nova forma de tratamento para pacientes com diabetes

The importance of the kidney in glucose homeostasis has been recognized for many years. Recent observations indicating a greater role of renal glucose metabolism in various physiologic and pathologic conditions have rekindled the interest in renal glucose handling as a potential target for the treatment of diabetes. The enormous capacity of the proximal tubular cells to reabsorb the filtered glucose load entirely, utilizing the sodium-glucose co-transporter system (primarily SGLT-2), became the focus of attention. Original studies conducted in experimental animals with the nonspecific SGLT inhibitor phlorizin showed that hyperglycemia after pancreatectomy decreased as a result of forced glycosuria. Subsequently, several compounds with more selective SGLT-2 inhibition properties (“second-generation”) were developed. Some agents made it into pre-clinical and clinical trials and a few have already been approved for commercial use in the treatment of type 2 diabetes. In general, a 6-month period of therapy with SGLT-2 inhibitors is followed by a mean urinary glucose excretion rate of ~80 g/day accompanied by a decline in fasting and postprandial glucose with average decreases in HgA1C ~1.0%. Concomitant body weight loss and a mild but consistent drop in blood pressure also have been reported. In contrast, transient polyuria, thirst with dehydration and occasional hypotension have been described early in the treatment. In addition, a significant increase in the occurrence of uro-genital infections, particularly in women has been documented with the use of SGLT-2 inhibitors. Conclusion: Although long-term cardiovascular, renal and bone/mineral effects are unknown SGLT-2 inhibitors, if used with caution and in the proper patient provide a unique insulin-independent therapeutic option in the management of obese type 2 diabetes patients. .

A importância do rim na homeostase de glicose é reconhecida desde há muitos anos. Observações recentes, indicando um papel maior do metabolismo renal da glicose em várias condições fisiológicas e patológicas, reavivaram o interesse no manuseio renal de glicose como um alvo em potencial para o tratamento do diabetes. A enorme capacidade das células tubulares proximais para reabsorver a carga total de glicose filtrada, utilizando o sistema de co-transporte de sódio e glicose (SGLT), tornou-se o foco de atenção. Estudos originais realizados em animais experimentais com o uso do inibidor não-específico da SGLT florizina, demonstraram que a hiperglicemia após pancreatectomia diminuiu como resultado de glicosúria forçada. Posteriormente, foram desenvolvidas diversas substâncias com propriedades mais seletivas de inibição da SGLT-2 ("segunda geração"). Vários agentes foram usados em ensaios pré-clínicos e clínicos, e alguns já foram aprovados para uso comercial no tratamento da diabetes tipo 2. Em geral, os dados clinicos mostram que um período de 6 meses de tratamento com inibidores da SGLT-2 é seguido por uma taxa de excreção de glicose urinária média de ~ 80 g/dia, acompanhado por uma queda na glicemia de jejum e pós-prandial e com redução média na HbA1C de - 1.0%. Também foram relatados perda concomitante no peso corpóreo e uma leve mas consistente queda da pressão arterial. Em contraste, eventos adversos transitórios como poliúria, sede com desidratação e hipotensão ocasional foram descritos na fase inicial de tratamento. Além disso, um aumento significativo na ocorrência de infecções urogenitais, particularmente em mulheres, foi documentado com o uso de inibidores da SGLT-2. Os efeitos ...

Genetic epidemiology of cardiometabolic risk factors and their clustering patterns in Mexican American children and adolescents: the SAFARI Study.

Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6-17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, TX, at increased risk of type 2 diabetes. MS was defined as ≥3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL-cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population.

Pioglitazone improvement of fasting and postprandial hyperglycaemia in Mexican-American patients with Type 2 diabetes: a double tracer OGTT study.

OBJECTIVES: By using tracer techniques, we explored the metabolic mechanisms by which pioglitazone treatment for 16 weeks improves oral glucose tolerance in patients with type 2 diabetes when compared to subjects without diabetes. METHODS: In all subjects, before and after treatment, we measured rates of tissue glucose clearance (MCR), oral glucose appearance (RaO) and endogenous glucose production (EGP) during a (4-h) double tracer oral glucose tolerance test (OGTT) (1-(14)C-glucose orally and 3-(3)H-glucose intravenously). Basal hepatic insulin resistance index (HepIR) was calculated as EGPxFPI. beta-cell function was assessed as the incremental ratio of insulin to glucose (DeltaI/DeltaG) during the OGTT. RESULTS: Pioglitazone decreased fasting plasma glucose concentration (10.5 +/- 0.7 to 7.8 +/- 0.6 mM, P < 0.0003) and HbA1c (9.7 +/- 0.7 to 7.5 +/- 0.5%, P < 0.003) despite increased body weight and no change in plasma insulin concentrations. This was determined by a decrease both in fasting EGP (20.0 +/- 1.1 to 17.3 +/- 0.8 micromol/kg(ffm) min, P < 0.005) and HepIR (from 8194 declined by 49% to 3989, P < 0.002). During the OGTT, total glucose Ra during the 0- to 120-min time period following glucose ingestion decreased significantly because of a reduction in EGP. During the 0- to 240-min time period, pioglitazone caused only a modest increase in MCR (P < 0.07) but markedly increased DeltaI/DeltaG (P = 0.003). The decrease in 2h-postprandial hyperglycaemia correlated closely with the increase in DeltaI/DeltaG (r = -0.76, P = 0.004) and tissue clearance (r = -0.74, P = 0.006) and with the decrease in HepIR (r = 0.62, P = 0.006). CONCLUSIONS: In diabetic subjects with poor glycaemic control, pioglitazone improves oral glucose tolerance mainly by enhancing the suppression of EGP and improving beta-cell function.

Relationship between vascular reactivity and lipids in Mexican-Americans with type 2 diabetes treated with pioglitazone.

CONTEXT: Vascular dysfunction and insulin resistance precede atherosclerosis in type 2 diabetes (T2DM). Better knowledge of the interaction between these is of considerable clinical interest. OBJECTIVE: The objective of this study was to examine the association between inflammation, glucose, and lipid metabolism and vascular dysfunction. DESIGN AND SETTING: We conducted a randomized, double-blind, controlled trial of pioglitazone vs. placebo and other therapies aimed at equal glycemic control for 24 wk at an academic tertiary referral clinic. PATIENTS AND INTERVENTIONS: Mexican-American subjects with T2DM and no complications were randomly assigned to pioglitazone 45 mg daily (PIO, n=16) or placebo (CON, n=15) and matched for age, gender, body mass index, diabetes duration, and glycemic control. All subjects completed the study. MAIN OUTCOME MEASURE: We looked for improved vascular reactivity independent of glycemic control but closely related to plasma adiponectin, lipids, and insulin sensitivity. RESULTS: After 24 wk, there was an equal decrease in fasting plasma glucose (approximately 135 mg/dl), glycosylated hemoglobin (approximately 7.0%), and glucose production (approximately 15%). The decrease in free fatty acids (30 vs. 10%) and increase in glucose disposal (40 vs. 25%) were greater in PIO vs. CON (P<0.05). In PIO, plasma high-density lipoprotein rose by 15% (P<0.05), and low-density lipoprotein and high-density lipoprotein particle size rose significantly (P<0.01). Plasma adiponectin doubled in PIO (from 6.1+/-0.8 to 12.7+/-2.1 microg/ml). Forearm blood flow rose equally (approximately 130%) during reactive hyperemia in both groups, although after therapy, the increase was greater (P<0.001) in PIO (153%) than in CON (137%); vasodilation was greater (P=0.01) in PIO (92, 160, and 204%) than in CON with acetylcholine (74, 130, and 144%) and with sodium nitroprusside (PIO=164 and 253% vs. 116 and 230%; P=0.04). The elevation in diameter was also greater in PIO (13 vs. 10%; P<0.05). Vascular responses correlated with plasma free fatty acids, adiponectin, and low-density lipoprotein particle size but not with glycemic control. CONCLUSION: These data indicate that pioglitazone improves vascular reactivity irrespective of glycemic control and suggest a close association with changes in fat cell metabolism.

Are the effects of branched chain amino acids and glucose infusions on nitrogen urinary excretion in a four postoperative period of adults rabbits, additive?

The effects of branched chain amino acid (BCAA) and BCAA plus glucose infusions in nitrogen urinary excretion, in a four day postoperative period, was investigated in rabbits. Thirty-two adults rabbits, male (New Zealand) were randomly assigned to four groups: Group I (control) received saline solution (0.98 percent NaCl); Group II received glucose infusion (1 g/Kg/day); Group III received BCAA infusion (1 g/Kg/day) and Group IV reveived BCAA plus glusoce (1 g/Kg/day). During the four days postoperative period all animals were fasted completely. Urinary total nitrogen excretion was calculated on each day. All results were expressed in grams of nitrogen per kilogram of body weight per day +- standard error of the mean (+- SEM). The infusion of BCAA was followed by a significant reduction in urinary nitrogen excretion when compared to both glucose and saline controls. This nitrogen sparing effect of BCAA infusion during postoperative period was observed in all four days following surgical procedures. Glucose infusion alone also induced a decrease in urinary nitrogen excretion during the four days postoperative period when compared to saline control group. The infusion of BCAA plus glucose was followed by a slight, but significant reduction in urinary nitrogen loss when compared to glucose saline controls. However, the nitrogen excretion in urine after BCAA plus glucose infusion was significantly higher than the nitrogen loss in urine of all animals receiving BCAA alone. We concluded that the nitrogen sparing effect following the infusion of BCAA plus glucose was less pronounced than nitrogen sparing effect of BCAA infusion alone

Dieta enteral elementar-hidrolisado de casina: estudo de avaliaçäo clínica / Elementary enteral diet-casein hydrolysate: study of clinical validation

O Laboratório Universitário Rodolpho Albino (LURA) da Universidade Federal Fluminense (UFF) vem desenvolvendo uma soluçäo de hidrolisado ácido de caseína com material, matéria-prima e tecnologia inteiramente nacionais. Neste trabalho de validade receberam, durante 166 dias, um gotejamento naso-enteral de uma mistura nutritiva contendo a soluçäo de hidrolisado ácido de caseína LURA-UFF como única fonte proteíca da dieta. Todos os pacientes hospitalizados por traumatismo crânio-encefálico, pancreatite aguda, hipertensäo arterial complicada, fístulas digestivas e neoplasias receberam suporte nutricional como coadjuvante do tratamento clínico ou cirúrgico. Com exceçäo de um paciente com diarréia, todos os demais pacientes demonstraram uma boa tolerância digestiva e näo apresentaram sinais de reaçäo clínica ao produto. Apesar de elevada osmolaridade total de algumas misturas nutritivas, näo se verificou nenhuma complicaçäo clínica. O exame microbiológico das amostras e o pH final da soluçäo estiveram dentro de padröes aceitáveis. Nosso trabalho, porém enfatiza a necessidade de cuidados especiais com os cateteres enterais, a infusäo e o armazenamento da mistura nutritiva final. A demonstraçäo da validade clínica e a avaliaçäo nutricional, em andamento, do hidrolisado ácido de caseína LURA-UFF para uso em nutriçäo enteral hospitalar representa uma conquista porque amplia a disponibilidade de soluçöes nutritivas e, principalmente, por introduzir um produto inteiramente brasileiro, econômico, prático e eficiente. Nossos resultados também provam que a integraçäo e o desenvolvimento de pesquisas interdepartamentais na UFF beneficiam a comunidade