Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (≥ 50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function

Regional differences in the management of cardiovascular risk factors among adults with diabetes: An evaluation of the Diabetes Collaborative Registry

AimsTo compare cardiovascular risk factor control in adults with diabetes participating in a national diabetes registry to those in the general population and to ascertain regional differences in diabetes care.MethodsAdults with diagnosed diabetes in the Diabetes Collaborative Registry (DCR) were compared with those in the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2016; standardized mean difference (SMD) > 0.2 defined significance. Regional differences were assessed in the DCR cohort; p < .05 defined significance.ResultsThe DCR cohort was older (61 vs. 57 years, SMD = 0.38), more insured (99.7% vs. 91.0%, SMD = 0.42), and less ethnically diverse (83% non-Hispanic white vs. 76%, SMD = 0.30) compared with NHANES. The proportion of overweight/obesity, A1c < 7% (<53 mmol/mol), and BP < 140/90 were similar, but DCR participants had higher proportion with LDL < 2.59 mmol/L (61% vs. 41%, SMD = 0.39) and fewer tobacco users (17% vs. 32%, SMD = 0.35). Regionally, obesity, lack of glycaemic control, and tobacco use were highest in the Midwest, BP control was the lowest in the South, and LDL control was lowest in the Northeast.ConclusionsSignificant regional differences in diabetes care delivery and outcomes were identified using a national diabetes registry. Serial analyses of the DCR may supplement national evaluations to deepen our understanding of diabetes care in the US

Bone health in subjects with type 1 diabetes for more than 50 years

AIMS: Few data regarding prevalence of and risk factors for poor bone health in aging individuals with long-standing T1D are available. In this study, we aim to describe the prevalence of bone fragility and to identify factors associated with low bone density in individuals with long-term T1D. METHODS: We examined the prevalence of non-vertebral fractures in 985 subjects enrolled in the Joslin 50-Year Medalist Study and measured bone mineral density (BMD) by dual-energy X-ray absorptiometry at the femoral neck, lumbar spine and radius in a subset (65 subjects, mean age 62.6 years, duration 52.5 years, HbA1c 7.1%) with no significant clinical or demographic differences from the rest of the cohort. RESULTS: Medalists have low prevalence of fractures (0.20% hip and 0.91% wrist) and normal Z-score values (spine +1.15, total hip +0.23, femoral neck -0.01, radius +0.26; p > 0.05 for differences vs. 0 at all sites). A significant relationship was found between lower BMD and higher total cholesterol, triglycerides and LDL levels, but not HbA1c. Low BMD at the femoral neck was associated with cardiovascular disease after adjustment for confounding factors: prevalence risk ratio of CVD [95% CI] 4.6 [1.2-18.1], p = 0.03. No other diabetic vascular complication was found to be associated with low BMD. CONCLUSIONS: These are the first data regarding bone health in aging individuals who have had diabetes for 50 or more years. The low rates of non-vertebral fractures and the normal Z-score suggest the long T1D diabetes duration did not increase the risk of bone fractures in Medalists compared to non-diabetic peers. Additionally, the association with cardiovascular disease demonstrates the BMD differences in groups are likely not due to glycemic control alon

Gyroscopic theory of the Foucault pendulum : new Berry phases and sensitivity to syzygies

The normal way of exploiting a Foucault pendulum is by considering the total precession angle described during a complete cycle and to cumulate those elementary precession increments in order to yield a macroscopic precession angle. Said precession angle has been shown by Hanney to constitute a geometric phase in the sense described by Berry in 1984. The above precession increments per cycle have also been described by Berry as the result of a mathematical two-form corresponding to a pair of orthogonal pendulum circular oscillation states. In this article, the pendulum is analyzed on a half-cycle basis, as a pair of contra-rotating gyroscopes spinning about a horizontal axis. During two consecutive half-cycles, these two gyroscopes, acting in sequence, describe equal precession angles about the vertical axis, but in opposite directions, when the horizontal axis is forced by gravity to change its orientation in free space as the Earth is revolving. That gives rise, within each complete cycle, to a novel 8-shaped orbit. The cumulative precession angle difference over many complete cycles constitutes a new geometric phase of the Berry type. It can be described by a new two-form corresponding to the spin states of the two contrarotating gyroscopes. Instead of evaluating the effect of the two-form after each complete oscillation cycle, the new two-form is assessed after each half cycle and the difference between the half-cycle effects is cumulated. The new geometric phase is related to the tilt rate of the local vertical in free space. Thanks to an 18-hourduration pendulum experiment, evidence of the novel 8-shaped orbit is given. The Foucault pendulum is no longer considered in its geocentric environment, but in the barycentre frame of different celestial bodies. Sensitivity to syzygies between pendulum and said celestial bodies is discussed