Diabetes, Obesity and Metabolism Now最新文献

Bariatric surgery is increasingly been utilized to induce and maintain significant weight loss among patients with obesity. For patients with diabetes, bariatric surgery is associated with increased likelihood of reversal of type 2 diabetes; however, its impact on long-term diabetes related neuropathic complications remain unclear. This is particularly relevant given the potential increased risk of “treatment-induced neuropathy” associated with rapid improvements of glucose control. A study undertaken by research team from the University of Michigan have now reported that bariatric surgery may improve neuropathy by regenerating damaged nerves. In the study published in the journal Diabetologia, 120 patients who underwent bariatric surgery for obesity were followed up for over 2 years after the procedure. Metabolic risk factors such as high glucose, high blood pressure and lipid levels were significantly improved. The researchers also assessed two primary measures for peripheral neuropathy in patients with obesity by undertaking skin biopsies to assess nerve fibre density in the thigh and the leg. They observed that 2 years after bariatric surgery, nerve fibre density improved in the thigh and remained stable in the leg. This is particularly relevant given that the natural history of peripheral neuropathy among patients with obesity is often associated with a decline in nerve function, thus, stability in nerve fibre density is considered to be a good outcome. Furthermore, the observed improvement in nerve fibre density at the thigh indicate that bariatric surgery may be a successful therapy to improve or reverse peripheral neuropathy for patients with long-term metabolic impairment. This finding advances current therapeutic options for peripheral neuropathy, especially in patients with obesity which currently focuses on analgesia and neuropathic oral treatment such as gabapentin, amitriptyline, duloxetive, topical analgesics and non-medical treatments, like acupuncture and cognitive behavioural therapy.

Increased evidence has emerged regarding the cardio- and renal protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitor. However, this class of therapy is also associated with potential increased risk of adverse effects–namely genito-urinary tract infection, dehydration and rarely, increased risks of DKA. Despite these potential adverse effects, little is known about their effects on hospitalization from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease. A recent sub-analysis of the DECLARE-TIMI trial assessed the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease. Between 2013 and 2018, 17 160 people were enrolled in the original trial, of whom 10 186 had multiple risk factors for atherosclerotic cardiovascular disease, and 6835 had both no evidence of atherosclerotic cardiovascular disease and low kidney disease risk. According to the results, dapagliflozin was associated with a lower risk of first non-elective hospitalization for any cause and total non-elective hospitalisations for any cause. The association between dapagliflozin use and the risk of first non-elective hospitalization for any cause was consistent in subgroups of participants with and without atherosclerotic cardiovascular disease at baseline. In addition, compared with the placebo group, the dapagliflozin group had lower risk of first hospitalisations due to cardiac disorders, metabolism and nutrition disorders, renal and urinary disorders, and due to any other cause excluding these three causes. Treatment with dapagliflozin was also associated with a lower risk of hospitalisations due to musculoskeletal and connective tissue disorders and infections. These findings might have important implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition.

In England, the NHS Diabetes Prevention Programme is offered to adults with pre-diabetes, with lifestyle advice to help reduce the risk of developing type 2 diabetes. The programme is intended to reduce the yearly cost of type 2 diabetes to the NHS by £8.8 billion, which is almost 9% of its budget, according to Diabetes UK.

People with pre-diabetes are particularly at high risk of developing type 2 diabetes mellitus. Researchers from the University of Manchester have therefore set out to investigate whether people who were referred to the programme were less likely to develop type 2 diabetes, compared with those who were not referred to the programme. To do this, the investigators used a cohort study of patients attending primary care in England using clinical Practice Research Datalink data from 1 April 2016 (NHS Diabetes Prevention Programme introduction) to 31 March 2020. Patients referred to the programme from referring practices were matched to patients in non-referring practices to minimize confounding. Patients were matched based on age, sex, and date of pre-diabetes diagnosis (within 365 days). Analysis was adjusted for age (at index date), sex, time from pre-diabetes diagnosis to index date, BMI, HbA1c, total serum cholesterol, systolic blood pressure, diastolic blood pressure, prescription of metformin, smoking status, socioeconomic status, a diagnosis of depression, and comorbidities.

A total of 18 470 patients referred to the NHS Diabetes Prevention Programme were matched with 51 331 patients not referred to NHS Diabetes Prevention Programme in the main analysis. Mean follow-up from referral was 482.0 and 472.4 days, respectively.

The researchers identified that the risk of developing type 2 diabetes was 20% lower in people with raised blood sugars referred to the programme, compared with people who were not referred and who received usual care.

While caution is needed to fully interpret the findings of this observational study, findings from the study supported the overall effectiveness of the programme. In addition, it would support the decision of the ‘rapid large-scale implementation’ of the programme in England, rather than a slower or regional introduction, as well as the continuation of the programme and the introduction of similar programmes to the rest of the United Kingdom.

Current guideline recommends at least a 150 min of moderate intensity activity a week (e.g., brisk walking, cycling or playing tennis) or 75 min of vigorous intensity activity a week, spread over 4–5 days a week to reduce risks of cardiovascular disease (CVD). Despite this modest recommendation, uptake for this level of activity remains low in the general population due to time commitments. A new study, published in the British Journal of Sports Medicine conducted by researchers from the MRC Epidemiology Unit at the University of Cambridge has set out to explore the amount of physical activity necessary to have a beneficial impact on several chronic diseases and premature death. One of the main aim is to understand the shape of the dose–response association between levels of physical activity with premature death and chronic disease outcomes.

To do this, researchers performed a systematic review and meta-analysis of 196 peer-reviewed articles, covering more than 30 million participants, from 94 large study cohorts. This, according to the investigators enabled them to produce the largest analysis to date of the association between physical activity levels and risk of heart disease, cancer, and early death.

From their analyses, they concluded that, apart from work-related physical activity, 2 in 3 people reported activity levels below 150 min per week of moderate-intensity activity, and fewer than 1 in 10 managed more than 300 min per week. Overall, higher activity levels of physical activities were associated with lower risks of all outcomes. Compared with inactive individuals, adults who achieved the 150 min of moderate-intensity activity had a 31% lower risk of all-cause mortality, a 29% lower risk of CVD mortality, and a 15% lower risk of cancer mortality. If all individuals accumulated at least 150 min a week, then 15.7%, 12.3%, and 7.1% of all-cause, CVD-related, and cancer-related deaths, respectively, would ‘potentially have been averted’. The researchers also calculated that if everyone in the studies had done the equivalent of at least 150 min per week of moderate-intensity activity, around 1 in 6 (15.7%) premature deaths, 1 in 9 (10.9%) cases of CVD, and 1 in 20 (5.2%) cases of cancer, would have been prevented.

They also found that ‘beyond’ 150 min per week of moderate-intensity activity, the additional benefits in terms of reduced risk of disease or early death were ‘marginal’. Importantly, even reducing the amount of physical activity by half also came with significant benefits. Accumulating 75 min per week of moderate-intensity activity brought with it a 23% lower risk of early death. If everyone managed at least 75 min per week of moderate-intensity physical activity, around 1 in 10 (10%) premature deaths, 1 in 20 (5%) cases of CVD, and nearly 1 in 30 (3%) cases of cancer, would be prevented. Seventy-five minutes per week of moderate activity was also enough to reduce the risk of developing CVD by 17% and

The link between high blood sugar levels and increased risk of  developing diabetic eye disease and blindness is very well established. However, the mechanism linking hypoglycaemia and progression of diabetic eye disease remains unclear.

A study published in the journal Cell Reports analysed protein levels in human and mouse retinal cells and intact retinas grown in an environment of low glucose in the laboratory, as well as in mice that experienced intermittent low blood sugar. They focused on retinal cells known as the Müller glial cells - which are supportive cells for neurons in the retina that relies primarily on glucose for energy production. These cells increased the expression of the GLUT1 gene, which makes a protein that facilitate the transport of glucose into cells for energy. The researchers found that low glucose levels in human and mouse retinal cells resulted in an increased level of a transcription factor, called hypoxia-inducible factor (HIF)-1α. This in turn led to an increase in the cellular production of the GLUT1 protein– needed to improve their ability to utilize available glucose, preserving the limited oxygen available for energy production by retinal neurons. However, in low-oxygen environments, such as in the retinas of patients with diabetic eye disease, this normal, physiologic response to low glucose triggered a flood of HIF-1α protein into the cells' nucleus. This resulted in an increase in the production of angiogenic factors such as VEGF and ANGPTL4, which cause the growth of abnormal, leaky blood vessels – the major mechanism of diabetic macular oedema. Based on this study, increased understanding of the HIF-1α pathway can lead to novel target for developing new treatments for diabetic eye disease.

Intermittent fasting diets, also known as Time Restricted Eating (TRE) have become popular in recent years as an effective weight loss method. TRE is a form of chrono nutrition that focuses on limiting calorie intake to a shortened “eating window”, followed by a prolonged fasting period (e.g. 8 hour feeding window, 16 hour fasting period). Initial time-restricted feeding studies on diet-induced obesity in mice demonstrated improved weight loss and metabolic parameters when eating duration was limited to 8 hours or less. TRE has since been investigated in humans with some evidence for effectiveness in reducing bodyweight and improving certain cardio-metabolic parameters. In this study, researchers conducted a 3-month TRE diet intervention among 36 people with diabetes and found almost 90% of participants, including those who took blood sugar-lowering agents and insulin, reduced their diabetes medication intake after TRE. Fifty-five percent of these people experienced diabetes remission, discontinued their diabetes medication and maintained it for at least one year. Importantly, sixty-five percent of the study participants who achieved diabetes remission had a diabetes duration of more than 6 years – disease duration >6 years was an exclusion criteria in the DIRECT study which reported diabetes remission following a Very Low calorie Diet programme. Overall this study provided preliminary evidence of efficacy of TRE for diabetes remission. It would be interesting to have a randomised controlled study of VLCD vs TRE with a primary outcome measure being rate of diabetes remission.

The study was published in the Endocrine Reviews and received funding from the National Natural Science Foundation of China.

There is significant interests in the role of gut microbiome on the risks of developing insulin resistance and type 2 diabetes. These microbiome is thought to be affected by medications and diet. Specifically, previous studies have shown that type 2 diabetes was associated with having lower levels of a certain type of bacteria that produce a type of fatty acid called butyrate. A prospective study led by investigators at Cedars-Sinai analysed associations between butyrate-producing taxa and detailed measures of insulin homeostasis, whose dysfunction underlies diabetes in 224 non-Hispanic Whites and 129 African Americans. Study participants were asked to attend three clinic visits and collect stool samples prior to the visits. They conducted genetic sequencing on the stool samples, for example, to study the participants' microbiomes, and specifically look for bacteria that previous studies have found to be associated with insulin resistance. Each participant also filled out a diet questionnaire and took an oral glucose tolerance test. The research team analyzed associations between 36 butyrate-producing bacteria found in the stool samples and a person's ability to maintain normal levels of insulin. They controlled for factors that could also contribute to a person's diabetes risk, such as age, sex, body mass index and race. The study, published in the peer-reviewed journal Diabetes, found people with higher levels of a bacterium called Coprococcus tended to have higher insulin sensitivity (β = 0.14; P = 0.002) and disposition index (β = 0.12; P = 0.012) and a lower rate of dysglycemia (odds ratio [OR] 0.91; 95% CI 0.85–0.97; P = 0.0025). Conversely, Flavonifractor was associated with lower insulin sensitivity (β = −0.13; P = 0.004) and disposition index (β = −0.11; P = 0.04) and higher prevalence of dysglycemia (OR 1.22; 95% CI 1.08–1.38; P = 0.0013). The study showed that although most butyrate producers analyzed appear to be metabolically beneficial, this is not the case for all such bacteria. Future therapeutic strategies to target, microbiome to prevent or treat diabetes should therefore targeted to specific butyrate-producing taxa rather than all butyrate producers.

Bariatric surgery procedures, namely Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) is increasingly used worldwide, have been shown to be the most effective strategy to induce and maintain weight loss as well as inducing long-term remission from type 2 diabetes among people with significant obesity. The mechanism for diabetes remission remains unclear and multi-factorial, although increased secretion of endogenous glucagon-like peptide 1 (GLP-1) hormones to improve postprandial β-cell function is widely considered to be the main mechanism for diabetes remission following RYGB. However, recent studies have shown that rate of remission between the two types of bariatric surgery procedures are similar but yet, the mechanism for remission above and beyond weight loss per se following SG is less clear. Beyond GLP-1, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. A study published in Diabetes Care have therefore studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in un-operated (CON), SG-operated, and RYGB-operated people with no history of diabetes. The investigator found that, as expected, postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. Interestingly, blockage of GLP-1R reduced β-cell glucose sensitivity and increased postprandial glucose responses in both surgical groups but had no effect in CON. Blockage of GIPR however reduced β-cell glucose sensitivity and increased postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. This study showed that while GLP-1 is the most important mediator of improved beta cell function after RYGB, both GLP-1 and GIP are equally important after SG. The combine benefits of GLP-1 and GIP following SG is interesting, given the recent emergence of the dual GLP-1 and GIP agonist for the treatment of diabetes and obesity. It would be interesting also to explore the relative role of Glucagon on beta cell function following both procedures.

Continuous Glucose Monitoring (CGM) technology has been increasingly used to replace pin-prick of blood sugar in order to monitor glucose control, helps meal planning and reduce risk of hypoglycaemia. Using this technology, assessment of “Time in Range”, “Time below range”, glucose trends as well as alerting patients to low glucose levels have become possible. While this has tremendously improved patients quality of life, long-term impact on clinical outcomes is still limited, especially in people with Type 2 Diabetes and in real life setting. An observational retrospective study was therefore undertaken within the Veteran Affairs Health Care system to determine the benefit of starting CGM in adult-onset type 1 Diabetes (T1D) and type 2 Diabetes (T2D) with regard to longer-term glucose control and serious clinical events. Using health care records, investigators, compare glucose control and hypoglycemia- or hyperglycemia-related admission to an emergency room or hospital and all-cause hospitalization and matched them by statistical methods to CGM nonusers over 12 months. The study included 5,015 people with T1D and 15,706 with T2D who are on insulin and receving CGM, with similar numbers of nonusers. These individuals identified from January 1, 2015 to December 31, 2020. The analysis showed that reduction in HbA1c levels were significantly greater in CGM users with T1D (−0.26%; 95% CI −0.33, −0.19%) and T2D (−0.35%; 95% CI −0.40, −0.31%) than in nonusers at 12 months. Percentages of patients achieving HbA1c <8 and <9% after 12 months were also greater in CGM users. Importantly also, in people with T1D, CGM significantly reduced risk of hypoglycaemia by about 31% and all-cause hospitalization by about 25%. Similarly among people with T2D, CGM users showed a significant 13% reduction in the risk of hyperglycemia and a significant 11% reduction in all-cause hospitalization. This study, which was derived from a large national cohort in the US showed further evidence to support the increase use of CGM to not only improve glucose control but to reduce risk of hypo-, hyperglycaema and all-cause hospitalization.

Heart disease is the leading cause of death worldwide and statin therapy has consistently shown in multiple landmark studies to reduce cardiovascular events and death. Despite the strength of evidence of its benefits, clinicians face many patients who are reluctant to start statin therapy. A new study published in the JAMA Network Open, by investigators from Brigham and Women's Hospital has conducted the first population-based study on patients’ non-acceptance of statin therapy recommendations. The study focused on high-risk patients who either had coronary artery or vascular disease, diabetes, high cholesterol levels, or previous history of stroke. All of these patients were recommended statins by their physicians, by virtue of their high cardiovascular risk in order to reduce their risk of heart attack and stroke and reduce cholesterol levels. The retrospective study included more than 24,000 patients who were seen at Mass General Brigham between Jan. 1, 2000, and Dec. 31, 2018. The study found that in patients at high risk of developing cardiovascular disease, more than 20 percent of patients refused to take statin medications. Interestingly, they observed that women were more likely than men to refuse statin therapy, by about 20%, and 50 percent more likely than men to never accept the recommendation. The study also showed that all patients who refused statin therapy developed higher LDL cholesterol levels.

Unfortunately, no data is available yet on whether nonacceptance of statin therapy wold adversely affect cardiovascular event rate such as heart attacks, strokes, and death. The study highlight the importance of targeting patients who decline statins by providing further education, understanding the reasons behind non-acceptance and devise strategies to further reduce patients cardiovascular disease risk.