The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials

AIMS/HYPOTHESIS: Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily. METHODS: Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio. RESULTS: A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, −0.67 to −0.81 mmol/l across treatments) and postprandial glucose (Day 5 to baseline AUC(0–t) ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC(0–t) ratio range: 1.6–1.9 for GLP-1 and 1.4–1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post-dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI −16%, −39%) lower bioavailability (least squares mean ratio of metformin AUC(0–24)) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values. CONCLUSIONS/INTERPRETATION: Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment. TRIAL REGISTRATION: Clinicaltrials.gov NCT01677299, NCT01804842 FUNDING: This study was funded by Elcelyx Therapeutics Inc. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-016-3992-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users

The ability of orthodontists and laypeople in the perception of gradual reduction of dentogingival exposure while smiling

OBJECTIVE: To assess differences in how orthodontists and laypersons perceive a reduction in dentogingival display on smiling. METHODS: Sixty examiners from both genders (30 laypersons and 30 orthodontists) evaluated photographs of spontaneous smiles of two subjects , one male and one female. Based on the original images, smile height was modified by means of an image manipulation software program. The examiners assigned scores ranging from 0 to 10, according to the level of pleasantness. Method reproducibility was examined using the Wilcoxon test, while the Friedman and Wilcoxon tests (p < 0.05) were employed to observe intra- and interexaminer differences, respectively. RESULTS: No differences were found between the groups of examiners - in terms of esthetics - in response to changes in smile height of both genders . However,men smile had lower acceptability than the women smile. A mild reduction in dentogingival display on smiling (2 mm) was not perceived by either laypersons or orthodontists (p > 0.05). CONCLUSIONS: women smiles achieved higher scores than men smiles however, samples involving a larger number of subjects in each group are required to ensure whether or not this finding is linked to the subjects gender.<br>OBJETIVO: avaliar a diferença na percepção de ortodontistas e leigos quanto à redução da exposição dentogengival no sorriso. MÉTODOS: no total, 60 avaliadores de ambos os sexos (30 leigos e 30 ortodontistas) avaliaram fotografias do sorriso espontâneo de dois indivíduos, um do sexo masculino e um do feminino. A partir das imagens originais, a altura do sorriso foi modificada usando-se um programa de manipulação de imagens. Os examinadores emitiram notas de 0 a 10, conforme o nível de agradabilidade. A reprodutibilidade do método foi examinada através do teste de Wilcoxon, enquanto os testes de Friedman e Wilcoxon (P<0,05) foram utilizados para observar as diferenças intra e interexaminadores, respectivamente. RESULTADOS: os resultados demonstraram não haver diferença entre os grupos de avaliadores com relação à estética quando a altura de ambos os sorrisos foi modificada. Entretanto, o sorriso do indivíduo do sexo masculino teve menor aceitabilidade do que o sorriso feminino. Uma suave redução na exposição dentogengival no sorriso (2mm) não foi percebida por leigos ou ortodontistas (p>0,05). CONCLUSÃO: o sorriso do indivíduo do sexo feminino recebeu notas mais altas do que o do masculino; entretanto, amostras envolvendo um maior número de indivíduos em cada grupo são necessárias para confirmar se a observação estaria relacionada ao sexo do indivíduo examinado