The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. In this study, we found that cells ...measure the degree of spatial confinement by using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, up-regulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler-based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development.
In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a ...useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice.
Movement of resources was essential to the survival and success of early complex societies. The sources and destinations of goods and the means of transportation - be it by boats, carts and/or foot - ...can often be inferred, but the logistics of these movements are inherently more difficult to ascertain. Here, we use strontium isotopic analysis to test hypotheses about the role of animal and animal-powered transport in medium and long-distance movement and exchange, using the Indus Civilization as a case study. Across the wide geographical spread of the Indus Civilisation, there is strong evidence for long-distance exchange of raw materials and finished objects and this process is presumed to involve boats and animal-driven transport, although there is little evidence as to the relative importance of each mode of movement. Strontium isotopic analysis of animal remains from four sites analysed for this study combined with results from nine other sites indicates limited long-distance animal movement between different geological zones within the Indus Civilisation. These findings suggest that individual animals primarily moved short- or medium-distances, though there are several significant exceptions seen in some pigs and cattle found at two large urban sites. We infer that long-distance transport of goods, be it raw materials, finished objects, other goods, or the animals themselves, could have occurred through the use of boats and waterways, by traction animals moving over long distances that did not end up in the archaeological record, and/or by different animals participating in many short to medium-distance movements.
Aims/hypothesis As adding metformin to insulin therapy has been advocated in type 1 diabetes, we conducted a systematic review of published clinical trials and clinical trial databases to assess the ...effects on HbA₁c, weight, insulin-dose requirement and adverse effects. Methods We constructed evidence tables and fitted a fixed-effects model (inverse variance method) in order to assess heterogeneity between studies and give a crude measure of each overall treatment effect. Results Of 197 studies identified, nine involved randomisation with informed consent of patients with type 1 diabetes to metformin (vs placebo or comparator) in either a parallel or crossover design for at least 1 week. We noted marked heterogeneity in study design, drug dose, age of participants and length of follow-up. Metformin was associated with reductions in: (1) insulin-dose requirement (5.7-10.1 U/day in six of seven studies); (2) HbA₁c (0.6-0.9% in four of seven studies); (3) weight (1.7-6.0 kg in three of six studies); and (4) total cholesterol (0.3-0.41 mmol/l in three of seven studies). Metformin was well tolerated, albeit with a trend towards increased hypoglycaemia. Formal estimates of combined effects from the five trials which reported appropriate data indicated a significant reduction in insulin dose (6.6 U/day, p < 0.001) but no significant reduction in HbA₁c (absolute reduction 0.11%, p = 0.42). No reported trials included cardiovascular outcomes. Conclusions/interpretation Metformin reduces insulin-dose requirement in type 1 diabetes but it is unclear whether this is sustained beyond 1 year and whether there are benefits for cardiovascular and other key clinical outcomes.
In 2011, the James Lind Alliance published a ‘top 10’ list of priorities for Type 1 diabetes research based on a structured consultation process. Whether reducing fluctuations in blood glucose can ...prevent long‐term microvascular and macrovascular complications was one of these. In this narrative review, 8 years on, we have assessed the updated evidence for the assertion that increased glucose variability plays an independent and clinically important role in the complications of Type 1 diabetes, over and above mean blood glucose and the effects of hypoglycaemia: the ‘glucose variability hypothesis’. Although studies in cultured cells and ex vivo vessels have been suggestive, most studies in Type 1 diabetes have been small and/or cross‐sectional, and based on ‘finger‐prick’ glucose measurements that capture glucose variability only in waking hours and are affected by missing data. A recent analysis of the Diabetes Control and Complications Trial that formally imputed missing data found no independent effect of short‐term glucose variability on long‐term complications. Few other high‐quality longitudinal studies have directly addressed the glucose variability hypothesis in Type 1 diabetes. We conclude that there is little substantial evidence to date to support this hypothesis in Type 1 diabetes, although increasing use of continuous glucose monitoring provides an opportunity to test it more definitively. In the meantime, we recommend that control of glycaemia in Type 1 diabetes should continue to focus on the sustained achievement of target HbA1c and avoidance of hypoglycaemia.
What's new?
Hyperglycaemia is the most important modifiable risk factor for both microvascular and macrovascular complications of Type 1 diabetes.
Intensive control of blood glucose can substantially prevent and delay these complications.
There is currently insufficient evidence to answer the James Lind research question ‘How tightly controlled do fluctuations in blood glucose need to be to reduce complications?’.
Efforts to reduce complications by improving glycaemic control in Type 1 diabetes should continue to focus on sustained achievement of target HbA1c and avoidance of hypoglycaemia.
More widespread use of continuous and flash glucose monitoring devices offers opportunities for more definitive research on this topic (both cohort and intervention studies).
Insulin-loaded microemulsions made by a reverse micellar approach improve the oral bioavailability of insulin with modest effects on blood glucose levels in diabetic rats.
Insulin loaded ...microemulsions were developed adopting a low shear reverse micellar approach using didoceyldimethylammonium bromide (DMAB) as the surfactant, propylene glycol (PG) as the co-surfactant, triacetin (TA) as the oil phase and insulin solution as the aqueous phase. A ternary phase diagram was constructed based on multiple cloud point titration to highlight the reverse micellar region. The droplet sizes of the microemulsions were 161.7
±
24.7
nm with PDI of 0.447
±
0.076 and insulin entrapment of ∼85%. Transmission electron microscopy (TEM) revealed the spherical nature and size homogeneity of the microemulsion droplets. The conformational stability of the entrapped insulin within microemulsions was confirmed by fluorescence spectroscopy and circular dichroism. The microemulsions displayed a 10-fold enhancement in bioavailability compared with plain insulin solution administered
per oral in healthy rats. The short-term
in vivo efficacy in STZ induced diabetic rats provided the proof of concept by a modest glucose reduction at a dose of 20
IU/kg. Together this preliminary data indicate the promise of microemulsions for oral delivery of insulin.
Aims/hypothesis
To describe the associations between age, sex and BMI at diagnosis of type 2 diabetes, and test the hypothesis that men are diagnosed with diabetes at lower average BMI than women of ...similar age.
Methods
Linear regression was used to estimate and compare the relationship between age and BMI at diagnosis among 51,920 men and 43,137 women included in a population-based diabetes register in Scotland for whom an index BMI measurement was taken within 1 year of diabetes diagnosis. We also examined HbA
1c
values by sex within the same timescale.
Results
Mean BMI closest to date of diagnosis of type 2 diabetes mellitus was 31.83 kg/m
2
(SD 5.13) in men and 33.69 kg/m
2
(SD 6.43) in women. The inverse relationship between age and BMI at diagnosis of type 2 diabetes mellitus was significantly steeper in women than in men (slope estimate in men −0.12 kg/m
2
per year 95% CI −0.13, −0.12 women −0.18 kg/m
2
per year 95% CI −0.18, −0.17,
p
< 0.0001 for formal test of interaction). Mean BMI difference was most marked at younger ages and narrowed with advancing age. However, HbA
1c
levels within 1 year of diagnoses were broadly similar in men and women.
Conclusions/interpretation
Men are diagnosed with type 2 diabetes at lower BMI than women across the age range. This observation may help explain why type 2 diabetes is more common among middle-aged men in populations of European extraction. Whether the same pattern is also observed in other ethnic groups requires confirmation.
Aims/hypothesis
Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture ...in women and men and compared the risk to that found with other drugs used in diabetes.
Methods
Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999–2008.
Results
There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28;
p
= 3 × 10
−5
), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%).
Conclusions/interpretation
Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.
PDF
