Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19

Objective: Although type 2 diabetes mellitus (T2DM) has been reported as a risk factor for coronavirus disease 2019 (COVID-19), the effect of pharmacologic agents used to treat T2DM, such as metformin, on COVID-19 outcomes remains unclear. Metformin increases the expression of angiotensin converting enzyme 2, a known receptor for severe acute respiratory syndrome coronavirus 2. Data from people with T2DM hospitalized for COVID-19 were used to test the hypothesis that metformin use is associated with improved survival in this population.Methods: Retrospective analyses were performed on de-identified clinical data from a major hospital in Wuhan, China, that included patients with T2DM hospitalized for COVID-19 during the recent epidemic. One hundred and thirty-one patients diagnosed with COVID-19 and T2DM were used in this study. The primary outcome was mortality. Demographic, clinical characteristics, laboratory data, diabetes medications, and respiratory therapy data were also included in the analysis.Results: Of these 131 patients, 37 used metformin with or without other antidiabetes medications. Among the 37 metformin-taking patients, 35 (94.6%) survived and 2 (5.4%) did not survive. The mortality rates in the metformin-taking group versus the non-metformin group were 5.4% (2/37) versus 22.3% (21/94). Using multivariate analysis, metformin was found to be an independent predictor of survival in this cohort (P = .02).Conclusion: This study reveals a significant association between metformin use and survival in people with T2DM diagnosed with COVID-19. These clinical data are consistent with potential benefits of the use of metformin for COVID-19 patients with T2DM.     

Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials

Background

The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality.

Methods and Findings

This meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal) against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients) were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR) = 0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR = 1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR = 0.90 (95% CI: 0.74 to 1.09); all strokes, RR = 0.76 (95% CI: 0.51 to 1.14); heart failure, RR = 1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR = 0.90 (95% CI: 0.46 to 1.78); leg amputations, RR = 1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR = 0.83 (95% CI: 0.59 to 1.17). For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I ² = 41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p = 0.10 and 0.02, respectively).

Conclusions

Although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality. Further studies are needed to clarify this situation. Please see later in the article for the Editors'' Summary     

Identifying Probable Diabetes Mellitus Among Hispanics/Latinos from Four U.S. Cities: Findings from the Hispanic Community Health Study/Study of Latinos

Objective: The aim of this study was to compare the ability of American Diabetes Association (ADA) diagnostic criteria to identify U.S. Hispanics/Latinos from diverse heritage groups with probable diabetes mellitus and assess cardiovascular risk factor correlates of those criteria.Methods: Cross-sectional analysis of data from 15,507 adults from 6 Hispanic/Latino heritage groups, enrolled in the Hispanic Community Health Study/Study of Latinos. The prevalence of probable diabetes mellitus was estimated using individual or combinations of ADA-defined cut points. The sensitivity and specificity of these criteria at identifying diabetes mellitus from ADA-defined prediabetes and normoglycemia were evaluated. Prevalence ratios of hypertension, abnormal lipids, and elevated urinary albumin-creatinine ratio for unrecognized diabetes mellitus—versus prediabetes and normoglycemia—were calculated.Results: Among Hispanics/Latinos (mean age, 43 years) with diabetes mellitus, 39.4% met laboratory test criteria for probable diabetes, and the prevalence varied by heritage group. Using the oral glucose tolerance test as the gold standard, the sensitivity of fasting plasma glucose (FPG) and hemoglobin A1c—alone or in combination—was low (18, 23, and 33%, respectively) at identifying probable diabetes mellitus. Individuals who met any criterion for probable diabetes mellitus had significantly higher (P<.05) prevalence of most cardiovascular risk factors than those with normoglycemia or prediabetes, and this association was not modified by Hispanic/Latino heritage group.Conclusion: FPG and hemoglobin A1c are not sensitive (but are highly specific) at detecting probable diabetes mellitus among Hispanics/Latinos, independent of heritage group. Assessing cardiovascular risk factors at diagnosis might prompt multitarget interventions and reduce health complications in this young population.Abbreviations:2hPG = 2-hour post–glucose load plasma glucoseADA = American Diabetes AssociationBMI = body mass indexCV = cardiovascularFPG = fasting plasma glucoseHbA1c = hemoglobin A1cHCHS/SOL = Hispanic Community Health Study/Study of LatinosHDL-C = high-density-lipoprotein cholesterolNGT = normal glucose toleranceNHANES = National Health and Nutrition Examination SurveyOGTT = oral glucose tolerance testTG = triglycerideUACR = urine albumin-creatinine ratio     

De-Intensification of Diabetes Treatment in Elderly Patients with Type 2 Diabetes Mellitus

Objective: De-intensification of diabetes treatment is recommended in elderly patients with tight glycemic control at high risk of hypoglycemia. However, rates of de-intensification in endocrine practice are unknown. We conducted a retrospective study to evaluate the rate of de-intensification of antidiabetic treatment in elderly patients with type 2 diabetes mellitus (T2DM) and tight glycemic control.Methods: All patients with ≥2 clinic visits over a 1-year period at a major academic diabetes center were included. De-intensification of diabetes treatment was defined as a decrease or discontinuation of any antidiabetic drug without adding another drug, or a reduction in the total daily dose of insulin or a sulfonylurea drug with or without adding a drug without risk of hypoglycemia.Results: Out of 3,186 unique patients, 492 were ≥65 years old with T2DM and hemoglobin A1c (HbA1c) <7.5% (<58 mmol/mol). We found 308 patients treated with a sulfonylurea drug or insulin, 102 of whom had hypoglycemia as per physician note. Among these 102 patients, 38 (37%) were advised to de-intensify therapy. In a subgroup analysis of patients ≥75 years old with HbA1c <7% (<53 mmol/mol), we found that out of 23 patients treated with a sulfonylurea drug or insulin and reporting hypoglycemia, 11 (43%) were advised de-intensification of therapy. There were no significant predictors of de-intensification of treatment.Conclusion: Our study suggests that de-intensification of antidiabetic medications is uncommon in elderly patients with T2DM. Strategies may need to be developed to prevent the potential harm of overtreatment in this population.Abbreviations: ADA = American Diabetes Association; CGM = continuous glucose monitoring; HbA1c = hemoglobin A1c; T2DM = type 2 diabetes mellitus; UKPDS = United Kingdom Prospective Diabetes Study     

Risk Factors for Hearing Impairment in Type 1 Diabetes

Objective: Studies have demonstrated that glycated hemoglobin (HbA1c) is a significant predictor of hearing impairment in type 1 diabetes. We identified additional factors associated with hearing impairment in participants with type 1 diabetes from the Diabetes Control and Complications Trial and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.Methods: A total of 1,150 DCCT/EDIC participants were recruited for the Hearing Study. A medical history, physical measurements, and a self-administered hearing questionnaire were obtained. Audiometry was performed by study-certified personnel and assessed centrally. Logistic regression models assessed the association of risk factors and comorbidities with speech- and high-frequency hearing impairment.Results: Mean age was 55 ± 7 years, duration of diabetes 34 ± 5 years, and DCCT/EDIC HbA1c 7.9 ± 0.9% (63 mmol/mol). In multivariable models, higher odds of speech-frequency impairment were significantly associated with older age, higher HbA1c, history of noise exposure, male sex, and higher triglycerides. Higher odds of high-frequency impairment were associated with older age, male sex, history of noise exposure, higher skin intrinsic florescence (SIF) as a marker of tissue glycation, higher HbA1c, nonprofessional/nontechnical occupations, sedentary activity, and lower low-density-lipoprotein cholesterol. Among participants who previously completed computed tomography and carotid ultrasonography, coronary artery calcification (CAC) >0 and carotid intima-medial thickness were significantly associated with high-but not speech-frequency impairment.Conclusion: Consistent with previous reports, male sex, age, several metabolic factors, and noise exposure are independently associated with hearing impairment. The association with SIF further emphasizes the importance of glycemia—as a modifiable risk factor—over time. In addition, the macrovascular contribution of CAC is novel and important.Abbreviations: AER = albumin excretion rate; CAC = coronary artery calcification; CVD = cardiovascular disease; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; eGFR = estimated glomerular filtration rate; ETDRS = Early Treatment Diabetic Retinopathy Study; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IMT = intima-media thickness; LDL = low-density lipoprotein; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; SIF = skin intrinsic fluorescence; T1D = type 1 diabetes     

The signal transduction pathway of PKC/NF-κB/c-fos may be involved in the influence of high glucose on the cardiomyocytes of neonatal rats

Background

Our aim was to compare the effects of a Paleolithic ('Old Stone Age') diet and a diabetes diet as generally recommended on risk factors for cardiovascular disease in patients with type 2 diabetes not treated with insulin.

Methods

In a randomized cross-over study, 13 patients with type 2 diabetes, 3 women and 10 men, were instructed to eat a Paleolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts; and a Diabetes diet designed in accordance with dietary guidelines during two consecutive 3-month periods. Outcome variables included changes in weight, waist circumference, serum lipids, C-reactive protein, blood pressure, glycated haemoglobin (HbA1c), and areas under the curve for plasma glucose and plasma insulin in the 75 g oral glucose tolerance test. Dietary intake was evaluated by use of 4-day weighed food records.

Results

Study participants had on average a diabetes duration of 9 years, a mean HbA1c of 6,6% units by Mono-S standard and were usually treated with metformin alone (3 subjects) or metformin in combination with a sulfonylurea (3 subjects) or a thiazolidinedione (3 subjects). Mean average dose of metformin was 1031 mg per day. Compared to the diabetes diet, the Paleolithic diet resulted in lower mean values of HbA1c (-0.4% units, p = 0.01), triacylglycerol (-0.4 mmol/L, p = 0.003), diastolic blood pressure (-4 mmHg, p = 0.03), weight (-3 kg, p = 0.01), BMI (-1 kg/m², p = 0.04) and waist circumference (-4 cm, p = 0.02), and higher mean values of high density lipoprotein cholesterol (+0.08 mmol/L, p = 0.03). The Paleolithic diet was mainly lower in cereals and dairy products, and higher in fruits, vegetables, meat and eggs, as compared with the Diabetes diet. Further, the Paleolithic diet was lower in total energy, energy density, carbohydrate, dietary glycemic load, saturated fatty acids and calcium, and higher in unsaturated fatty acids, dietary cholesterol and several vitamins. Dietary GI was slightly lower in the Paleolithic diet (GI = 50) than in the Diabetic diet (GI = 55).

Conclusion

Over a 3-month study period, a Paleolithic diet improved glycemic control and several cardiovascular risk factors compared to a Diabetes diet in patients with type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT00435240.     

Weight Gain and Management Concerns in Patients on Insulin Therapy

Background: The benefits of tight glycemic control in preventing the onset and progression of microvascular complications in patients with type 2 diabetes mellitus (DM) are unarguable. The majority of patients with type 2 DM will eventually require insulin to achieve adequate glycemic control. Using insulin earlier rather than later in the course of type 2 DM may diminish the deleterious effects of hyperglycemia on β-cell function and therefore help prolong good glycemic control and prevent the occurrence of microvascular complications. However, weight gain is a potential adverse effect of insulin therapy.Objective: The goal of this article was to describe the benefit of insulin therapy early in the course of type 2 DM, review the association of weight gain with insulin therapy, and examine potential detrimental effects that insulin-associated weight gain could have in patients with type 2 DM.Methods: Materials used for this article were identified through a search of MEDLINE (1966–2006). English-language articles were chosen using the search terms diabetes mellitus type 2, insulin, and obesity.Results: Intensive insulin therapy is often associated with weight gain. Although there is concern that weight gain in patients with type 2 DM may have adverse effects on risk factors for cardiovascular disease, unfavorable changes in blood pressure and lipid levels have not been consistently observed in clinical trials. Furthermore, clinical evidence, including data from the United Kingdom Prospective Diabetes Study, supports the view that intensive insulin therapy does not increase the risk for cardiovascular disease.Conclusions: Early insulin therapy in patients with type 2 DM may be a strategy that will help patients achieve and maintain good glycemic control, thereby reducing the risk of developing microvascular complications. Although weight gain is commonly associated with insulin therapy, it does not appear to put these patients at greater risk for cardiovascular disease.     

二甲双胍在II型糖尿病合并肝癌中的研究进展

多年来二甲双胍以其安全性高、价格低及疗效好的优点而广泛应用于临床治疗糖尿病。糖尿病增加了肝癌的罹患率并影响其预后。近年来研究发现二甲双胍在治疗Ⅱ型糖尿病(T2MD)患者时亦降低了其罹患肝癌的风险,大量研究证明其具有抗癌及协同抗癌作用。现本文对二甲双胍在Ⅱ型糖尿病患者中对肝癌发生的影响进行探讨,对二甲双胍抑制肿瘤的分子生物学机制进行了介绍,列举了最新的实验研究数据,并对现有临床数据进行分析,对于二甲双胍未来的研究方向提出了预期,对于二甲双胍未来在Ⅱ型糖尿病患者中肝癌的预防作用进行了简要的总结及未来使用的展望,对于其在Ⅱ型糖尿病合并肝癌的患者中的治疗作用进行了前瞻性的探讨,为二甲双胍在其他癌症防治中的应用提出了可能性。     

Metformin Suppresses Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-+Leprdb/+Leprdb Mice

Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-+Lepr^db/+Lepr^db (db/db) obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR), and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.     

Potential Place of SGLT2 Inhibitors in Treatment Paradigms for type 2 Diabetes Mellitus

Objective: Following the first Food and Drug Administration (FDA) approval in 2013, sodium glucose cotransporter 2 (SGLT2) inhibitors have generated much interest among physicians treating patients with type 2 diabetes mellitus (T2DM). Here, the role in treatment with this drug class is considered in the context of T2DM treatment paradigms.Methods: The clinical trials for the SGLT2 inhibitors are examined with a focus on canagliflozin, dapagliflozin, and empagliflozin.Results: Evidence from clinical trials in patients with T2DM supports the use of SGLT2 inhibitors either as monotherapy or in addition to other glucose-lowering treatments as adjuncts to diet and exercise, and we have gained significant clinical experience in a relatively short time.Conclusion: The drugs appear to be useful in a variety of T2DM populations, contingent primarily on renal function. Most obviously, SGLT2 inhibitors appear to be well suited for patients with potential for hypoglycemia or weight gain. In clinical trials, patients treated with SGLT2 inhibitors have experienced moderate weight loss and a low risk of hypoglycemic events except when used in combination with an insulin secretagogue. In addition, SGLT2 inhibitors have been shown to reduce blood pressure, so they may be beneficial in patients with T2DM complicated by hypertension. SGLT2 inhibitors were incorporated into the 2015 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement on the management of hyperglycemia and received an even more prominent position in the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive diabetes management guidelines and algorithm.Abbreviations: AE = adverse event A1C = glycated hemoglobin CI = confidence interval CKD = chronic kidney disease DKA = diabetic ketoacidosis DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate FDA = Food and Drug Administration FPG = fasting plasma glucose GLP-1 = glucagon-like peptide 1 HDL-C = high-density lipoprotein cholesterol HR = hazard ratio LADA = late-onset autoimmune diabetes of adulthood LDL-C = low-density lipoprotein cholesterol MACE = major adverse cardiovascular events SGLT1 = sodium glucose cotransporter 1 SGLT2 = sodium glucose cotransporter 2 T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus UACR = urine albumin to creatinine ratio     

Greater Low-Density Lipoprotein Cholesterol Variability Increases the Risk of Cardiovascular Events in Patients with Type 2 Diabetes Mellitus

Objective: Variability in lipid levels has been associated with poor cardiovascular outcomes in patients with coronary artery disease. The aim of this study was to investigate whether low-density lipoprotein cholesterol (LDLC) variability can be used to predict cardiovascular events in patients with type 2 diabetes mellitus (DM).Methods: A total of 5,354 patients with type 2 DM were enrolled in this study. Cardiovascular events including peripheral arterial disease, coronary artery disease, stroke, and cardiovascular death were defined as the study endpoints, and standard deviations of lipid levels were used to define intra-individual lipid variability.Results: Univariate Cox proportional hazards analysis showed that LDL-C standard deviation (hazard ratio &lsqb;HR] = 1.016; 95% confidence interval &lsqb;CI] = 1.006 to 1.022; P<.001) was associated with a higher risk of cardiovascular events. Multivariate Cox proportional hazards analysis showed that an increase in LDL-C standard deviation significantly increased the risk of cardiovascular events (HR = 1.063; 95% CI = 1.025 to 1.102; P = .01). Kaplan-Meier analysis of cardiovascular event-free survival showed that the patients in tertiles 2 and 3 of the standard deviation of LDL-C had worse cardiovascular event-free survival compared to those in tertile 1.Conclusion: Variability in LDL-C could predict cardiovascular events in the patients with type 2 DM in this study.Abbreviations: CAD = coronary artery disease; CI = confidence interval; CVD = cardiovascular disease; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; HbA1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; KMUHRD = Kaohsiung Medical University Hospital Research Database; LDL-C = low-density lipoprotein cholesterol; SD = standard deviation; UACR = urine albumin to creatinine ratio     

Utility of Psychological Screening of Young Adults with Type 1 Diabetes Transitioning to Adult Providers

Objective: Screening for depression, diabetes distress, and disordered eating in youth with type 1 diabetes (T1D) is recommended, as these comorbidities contribute to poor glycemic control. No consensus exists on which measures are optimal, and most previous studies have used nondisease-specific measures. We examined the utility of screening for these disorders using two disease-specific and one general measure at the time of transition from pediatric to adult care.Methods: Forty-three young adults from a T1D transition clinic completed the Patient Health Questionnaire, the Diabetes Distress Scale, and the Diabetes Eating Problem Survey–Revised. Chart review determined if clinicians noted similar symptoms during the year prior to transition. Metabolic data were also recorded.Results: Chart review identified 5 patients with depressive symptoms and 8 patients with diabetes distress. Screening identified 2 additional patients with depressive symptoms and 1 additional patient with diabetes distress. Of those noted to have symptomatic depression or diabetes distress on chart review, several subsequently screened negative on transition. Disordered eating was not detected by chart review, but 23.5% screened positive on transition. While depression, diabetes distress, and disordered eating positively correlated with glycated hemoglobin (HbA1c) (r = 0.31, P = .05; r = 0.40, P = .009; r = 0.63, P<.001, respectively), disordered eating accounted for the majority of observed variance (df = 1; F = 18.6; P<.001). Even though HbA1c was higher in patients with versus without disordered eating (P<.001), body mass index did not differ between the 2 groups (P = .51).Conclusion: In young adults with T1D, formal screening provides an opportunity to detect psychological problems, which, when treated, may help optimize metabolic control during the transition process.Abbreviations:T1D = type 1 diabetesHbA1C = hemoglobin A1cYCDP = Yale Children's Diabetes ProgramPHQ-8 = Patient Health Questionnaire–8DDS = Diabetes Distress ScaleDEPS-R = Diabetes Eating Problem Survey–Revised     

Goals for Medical Treatment in Obesity and Prediabetes: Improving Outcomes for Both

Objective: The purpose of this review is to expose the surprising prevalence of diabetes-related complications in people with persistent prediabetes, and hence, to expand the paradigm of diabetes prevention to include the prevention of complications related to both hyperglycemia and obesity.Methods: Published literature was reviewed.Results: Approximately 84 million Americans have prediabetes, 85% of whom are overweight or obese. Although the incidence of diabetes-related complications is lower in people with prediabetes versus those with type 2 diabetes, the overall prevalence is virtually identical. Furthermore, many people with prediabetes not only suffer from the complications related to hyperglycemia, they also experience complications of obesity. Treating obesity as a disease has the potential to prevent complications of both hyperglycemia and obesity. Emerging data reveal the untapped potential for clinicians to enhance the effectiveness of anti-obesity medications through a mindful health care delivery style. This involves an understanding and ethical utilization of the placebo effect in conjunction with active medical therapy. This approach is not intended to mislead patients but rather to activate neurocircuitry that synergizes with the central action of the approved anti-obesity medications to potentiate weight loss.Conclusion: Mindful administration of anti-obesity medications has the potential for widespread health benefits in people with obesity and prediabetes.Abbreviations: ADA = American Diabetes Association; DPP = Diabetes Prevention Program; CVD = cardiovascular disease     

Nonalcoholic Fatty Liver Disease and Risk of Diabetes: A Prospective Study in China

Objective: We aimed to investigate whether liver steatosis severity affects the risk of developing diabetes in a large cohort study.Methods: We prospectively examined the association in 41,650 Chinese adults with negative hepatitis-B surface antigen who were free of alcohol consumption, diabetes, and liver cirrhosis at baseline. Cox proportional models were used to estimate the risk of diabetes after a mean of 3.6 years of follow-up. Nonalcoholic fatty liver disease (NAFLD) was assessed with hepatic ultrasonography. Elevated alanine transaminase (ALT) was defined as ALT concentrations >19 and >30 U/L in females and males, respectively. Diabetes was defined as a fasting glucose ³7.0 mmol/L or treatment with hypoglycemic medication.Results: Liver steatosis severity was significantly associated with higher risks of developing diabetes (adjusted hazard ratio [HR] for severe vs. without NAFLD = 2.66, 95% confidence interval [CI]: 2.17–3.25, P-trend<.001) and impaired fasting glucose (fasting glucose between 5.6 and 6.9 mmol/L, adjusted HR = 1.36, 95% CI: 1.16–1.59, P-trend<.001), as well as a faster increase rate of fasting glucose concentrations (P-trend<.001), during 3.6 years of follow-up. Elevated ALT was also associated with incident diabetes (HR = 1.12, 95% CI: 1.02–1.22), adjusting for NAFLD and other covariates.Conclusion: We observed a dose-response relationship between liver steatosis severity and increased diabetes risk, and ALT may predict incident diabetes independently of NAFLD.Abbreviations: ALT = alanine transaminase; BP = blood pressure; CI = confidence interval; HCV = hepatitis C virus; HR = hazard ratio; IFG = impaired fasting glucose; NAFLD = nonalcoholic fatty liver disease; ULN = upper limit of normal     

Metformin Prevents and Reverses Inflammation in a Non-Diabetic Mouse Model of Nonalcoholic Steatohepatitis

Background

Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model.

Methodology/Principal Findings

Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH.

Conclusions/Significance

These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance.     

Menstrual and Reproductive Function in Women With Type 1 Diabetes

Objective: Menstrual irregularities, reproductive abnormalities, and androgen excess are reported to be more prevalent in women with type 1 diabetes (T1D). The objective of this study was to investigate the prevalence of menstrual irregularities, reproductive abnormalities, and androgen excess among women with T1D and their age-matched controls.Methods: A survey requesting information regarding menstrual and reproductive histories was administered to all participants. Results were stratified according to age (18 to 40, 40 to 50, and >50 years).Results: There were no significant differences between women with and without diabetes in age at menarche, cycle length, or androgen excess in any group. Women who self-reported difficulty with glycemic control were more likely to report irregular menses than controls (P = .04). Among women who reported ever being pregnant, there were fewer pregnancies (P = .02) and live births (P = .002) in women with T1D. Women with T1D reported a lower frequency of oral contraceptive use (P = .003), despite being less likely to smoke (P = .016).Conclusion: Menstrual and reproductive abnormalities were not observed more frequently in women with T1D in this study. Subtle but measurable differences in menstrual and reproductive function were confined to the subgroup of women who perceived poor control of their diabetes. Additional prospective studies of T1D and menstrual and reproductive function would be useful.Abbreviations: BMI = body mass index CVD = cardiovascular disease DCCT = Diabetes Control and Complications Trial FAD = Familial Autoimmune and Diabetes HbA_1c = glycated hemoglobin HC = hormonal contraception T1D = type 1 diabetes     

Risk Factors for Hypoglycemia in Inpatients with Total Parenteral Nutrition and Type 2 Diabetes: A Post HOC Analysis of the Insupar Study

Objective: Treatment of hyperglycemia with insulin is associated with increased risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients receiving total parenteral nutrition (TPN). The aim of this study was to determine the predictors of hypoglycemia in hospitalized T2DM patients receiving TPN.Methods: Post hoc analysis of the INSUPAR study, which is a prospective, open-label, multicenter clinical trial of adult inpatients with T2DM in a noncritical setting with indication for TPN.Results: The study included 161 patients; 31 patients (19.3%) had hypoglycemic events, but none of them was severe. In univariate analysis, hypoglycemia was significantly associated with the presence of diabetes with end-organ damage, duration of diabetes, use of insulin prior to admission, glycemic variability (GV), belonging to the glargine insulin group in the INSUPAR trial, mean daily grams of lipids in TPN, mean insulin per 10 grams of carbohydrates, duration of TPN, and increase in urea during TPN. Multiple logistic regression analysis showed that the presence of diabetes with end-organ damage, GV, use of glargine insulin, and TPN duration were risk factors for hypoglycemia.Conclusion: The presence of T2DM with end-organ damage complications, longer TPN duration, belonging to the glargine insulin group, and greater GV are factors associated with the risk of hypoglycemia in diabetic noncritically ill inpatients with parenteral nutrition.Abbreviations: ADA = American Diabetes Association; BMI = body mass index; CV% = coefficient of variation; DM = diabetes mellitus; GI = glargine insulin; GV = glycemic variability; ICU = intensive care unit; RI = regular insulin; T2DM = type 2 diabetes mellitus; TPN = total parenteral nutrition     

Development and Validation of a Novel Tool to Predict Hospital Readmission Risk Among Patients with Diabetes

Objective: To develop and validate a tool to predict the risk of all-cause readmission within 30 days (30-d readmission) among hospitalized patients with diabetes.Methods: A cohort of 44,203 discharges was retrospectively selected from the electronic records of adult patients with diabetes hospitalized at an urban academic medical center. Discharges of 60% of the patients (n = 26,402) were randomly selected as a training sample to develop the index. The remaining 40% (n = 17,801) were selected as a validation sample. Multivariable logistic regression with generalized estimating equations was used to develop the Diabetes Early Readmission Risk Indicator (DERRI™).Results: Ten statistically significant predictors were identified: employment status; living within 5 miles of the hospital; preadmission insulin use; burden of macrovascular diabetes complications; admission serum hematocrit, creatinine, and sodium; having a hospital discharge within 90 days before admission; most recent discharge status up to 1 year before admission; and a diagnosis of anemia. Discrimination of the model was acceptable (C statistic 0.70), and calibration was good. Characteristics of the validation and training samples were similar. Performance of the DERRI™ in the validation sample was essentially unchanged (C statistic 0.69). Mean predicted 30-d readmission risks were also similar between the training and validation samples (39.3% and 38.7% in the highest quintiles).Conclusion: The DERRI™ was found to be a valid tool to predict all-cause 30-d readmission risk of individual patients with diabetes. The identification of high-risk patients may encourage the use of interventions targeting those at greatest risk, potentially leading to better outcomes and lower healthcare costs.Abbreviations:DERRI™ = Diabetes Early Readmission Risk IndicatorICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical ModificationGEE = generalized estimating equationsROC = receiver operating characteristic     

Considerations for Gut Microbiota and Probiotics in Patients with Diabetes Amidst the Covid-19 Pandemic: A Narrative Review

Objective: To review data implicating microbiota influences on Coronavirus Disease 2019 (COVID-19) in patients with diabetes.Methods: Primary literature review included topics: “COVID-19,” “SARS,” “MERS,” “gut micro-biota,” “probiotics,” “immune system,” “ACE2,” and “metformin.”Results: Diabetes was prevalent (~11%) among COVID-19 patients and associated with increased mortality (about 3-fold) compared to patients without diabetes. COVID-19 could be associated with worsening diabetes control and new diabetes diagnosis that could be linked to high expression of angiotensin-converting enzyme 2 (ACE2) receptors (coronavirus point of entry into the host) in the endocrine pancreas. A pre-existing gut microbiota imbalance (dysbiosis) could contribute to COVID-19–related complications in patients with diabetes. The COVID-19 virus was found in fecal samples (~55%), persisted for about 5 weeks, and could be associated with diarrhea, suggesting a role for gut dysbiosis. ACE2 expressed on enterocytes and colonocytes could serve as an alternative route for acquiring COVID-19. Experimental models proposed some probiotics, including Lactobacillus casei, L. plantarum, and L. salivarius, as vectors for delivering or enhancing efficacy of anti-coronavirus vaccines. These Lactobacillus probiotics were also beneficial for diabetes. The potential mechanisms for interconnections between coronavirus, diabetes, and gut microbiota could be related to the immune system, ACE2 pathway, and metformin treatment. There were suggestions but no proof supporting probiotics benefits for COVID-19 infection.Conclusion: The data suggested that the host environment including the gut microbiota could play a role for COVID-19 in patients with diabetes. It is a challenge to the scientific community to investigate the beneficial potential of the gut microbiota for strengthening host defense against coronavirus in patients with diabetes.     

The Associations Between Hypovitaminosis D,Higher Pth Levels With Bone Mineral Densities,And Risk Of The 10-Year Probability Of Major Osteoporotic Fractures In Chinese Patients With T2Dm

Objective: In the current study, we investigated the vitamin D status, and its relationships with parathyroid hormone (PTH) levels, bone mineral density (BMD), and the 10-year probability of fractures in Chinese patients with type 2 diabetes mellitus (T2DM).Methods: This was a cross-sectional study of 785 patients. BMDs at the lumbar spine (L2-4), femoral neck (FN), and total hip (TH) were measured by dual-energy X-ray absorptiometry (DXA). Serum levels of 25-hydroxyvitamin D (25(OH)D) and intact PTH were also quantified. The 10-year probability of fracture risk (major osteoporotic fracture &lsqb;MOF] and hip fracture &lsqb;HF]) was assessed using the fracture risk assessment tool (FRAX).Results: The prevalence of vitamin D deficiency was 82.3%, and the mean 25(OH)D level was 36.9 ± 15.2 nmol/L. The adequate group had higher BMDs at the FN and TH and lower MOF risk than the inadequate groups. Lower 25(OH)D was associated with higher PTH (r = -0.126, P<.001). PTH was negatively correlated with BMDs at 3 sites and positively correlated with MOF and HF, but this relationship disappeared in the adequate subgroup. Multivariate stepwise regression analysis revealed that PTH was the determinant of MOF (standard β = 0.073, P = .010) and HF (standard β = 0.094, P = .004).Conclusion: Our results identified a significantly high rate of vitamin D deficiency among Chinese patients with T2DM. PTH is an important risk factor responsible for the higher 10-year probability of osteoporotic fractures in diabetic patients, especially in those with lower vitamin D levels.Abbreviations: AKP = alkaline phosphatase; ALB = serum albumin; BMD = bone mineral density; BMI = body mass index; Ca = calcium; CKD = chronic kidney disease; Cr = creatinine; FN = femoral neck; FRAX = fracture risk assessment tool; HbA1c = glycated hemoglobin A1c; HF = hip fracture; L2-4 = lumbar spine; MOF = major osteoporotic fracture; 25(OH)D = 25-hydroxyvitamin D; P = phosphorus; PTH = parathyroid hormone; T2DM = type 2 diabetes mellitus; TH = total hip; UA = uric acid