Role of vitamin D in diabetes mellitus and chronic kidney disease

Approximately 30%-50% of people are recognized to have low levels of vitamin D,and insufficiency and deficiency of vitamin D are recognized as global health problems worldwide.Although the presence of hypovitamin D increases the risk of rickets and fractures,low vitamin D levels are also associated with hypertension,cancer,and cardiovascular disease.In addition,diabetes mellitus(DM) and chronic kidney disease(CKD) are also related to vitamin D levels.Vitamin D deficiency has been linked to onset and progression of DM.Although in patients with DM the relationship between vitamin D and insulin secretion,insulin resistance,and β-cell dysfunction are pointed out,evidence regarding vitamin D levels and DM is contradictory,and well controlled studies are needed.In addition,vitamin D influences the renin-angiotensin system,inflammation,and mineral bone disease,which may be associated with the cause and progression CKD.There is increasing evidence that vitamin D deficiency may be a risk factor for DM and CKD;however,it remains uncertain whether vitamin D deficiency also predisposes to death from DM and CKD.Although at this time,supplementation with vitamin D has not been shown to improve glycemic control or prevent incident DM,clinical trials with sufficient sample size,study periods,and optimal doses of vitamin D supplementation are still needed.This review focuses on the mechanism of vitamin D insufficiency and deficiency in DM or CKD,and discusses the current evidence regarding supplementation with vitamin D in patients with these diseases.     

Chromium does not belong in the diabetes treatment arsenal: Current evidence and future perspectives

Chromium is considered to have positive effects on insulin sensitivity and is marketed as an adjunctive therapy for inducing glucose tolerance in cases of insulin resistance("the glucose tolerance factor"). Case reports on patients who received prolonged parenteral nutrition indeed showed that the absence of trivalent chromium caused insulin resistance and diabetes. However, whether patients with type 2 diabetes can develop a clinically relevant chromium deficiency is unclear. This review summarizes the available evidence regarding the potential effectiveness of chromium supplementation on glycemic control(Hemoglobin A1c levels) in patients with type 2 diabetes. No studies investigating the longterm safety of chromium in humans were found. All clinical trials that have been performed had a relative short follow-up period. None of the trials investigated whether the patients had risk factors for chromium deficiency.The evidence from randomized trials in patients with type 2 diabetes demonstrated that chromium supplementation does not effectively improve glycemic control. The meta-analyses showed that chromium supplementation did not improve fasting plasma glucose levels. Moreover, there were no clinically relevant chromium effects on body weight in individuals with or without diabetes. Future studies should focus on reliable methods to estimate chromium status to identify patients at risk for pathological alterations in their metabolism associated with chromium deficiency. Given the present data, there is no evidence that supports advising patients with type 2 diabetes to take chromium supplements.     

Magnesium and type 2 diabetes

Type 2 diabetes is frequently associated with both extracellular and intracellular magnesium(Mg) deficits. A chronic latent Mg deficit or an overt clinical hypomagnesemia is common in patients with type 2 diabetes, especially in those with poorly controlled glycemic profiles. Insulinand glucose are important regulators of Mg metabolism. Intracellular Mg plays a key role in regulating insulin action, insulin-mediated-glucose-uptake and vascular tone. Reduced intracellular Mg concentrations result in a defective tyrosine-kinase activity, postreceptorial impairment in insulin action and worsening of insulin resistance in diabetic patients. A low Mg intake and an increased Mg urinary loss appear the most important mechanisms that may favor Mg depletion in patients with type 2 diabetes. Low dietary Mg intake has been related to the development of type 2 diabetes and metabolic syndrome. Benefits of Mg supplementation on metabolic profiles in diabetic patients have been found in most, but not all clinical studies and larger prospective studies are needed to support the potential role of dietary Mg supplementation as a possible public health strategy in diabetes risk. The aim of this review is to revise current evidence on the mechanisms of Mg deficiency in diabetes and on the possible role of Mg supplementation in the prevention and management of the disease.     

The effect of magnesium supplements on early post‐transplantation glucose metabolism: a randomized controlled trial

Post‐transplantation hypomagnesemia is common and predicts diabetes. Magnesium improves glycemic control in diabetics and insulin sensitivity in insulin resistant subjects. We aimed to assess the effectiveness of oral magnesium for improving glycemic control and insulin sensitivity at 3 months post‐transplantation. We conducted a single‐center, open‐label, randomized parallel group study. We included adults with serum magnesium <1.7 mg/dl within 2 weeks after kidney transplantation. We randomized participants to 450 mg magnesium oxide up to three times daily or no treatment. The primary endpoint was the mean difference in fasting glycemia. Secondary endpoints were the mean difference in area under the curve (AUC) of glucose during an oral glucose tolerance test and insulin resistance measured by Homeostasis Model of Assessment‐Insulin Resistance (HOMA‐IR). Analyses were on intention‐to‐treat basis. In patients randomized to magnesium oxide (N = 27) versus no treatment (N = 27), fasting glycemia on average was 11.5 mg/dl lower (95% CI 1.7 to 21.3; P = 0.02). There was no difference between the two groups neither for 2 h AUC, where the mean value was 1164 mg/dl/min (95% CI ?1884 to 4284; P = 0.45) lower in the treatment group nor for HOMA‐IR. Magnesium supplements modestly improved fasting glycemia without effect on insulin resistance. Higher baseline glycemia among patients in the control group may have driven the positive outcome (ClinicalTrials.gov number: NCT01889576).     

FOXO1 Mediates Vitamin D Deficiency–Induced Insulin Resistance in Skeletal Muscle

Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin‐resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency–induced insulin resistance and DM2 remain unknown. Skeletal muscle insulin resistance is a primary defect in the majority of patients with DM2. Although sustained activation of forkhead box O1 (FOXO1) in skeletal muscle causes insulin resistance, a relationship between vitamin D deficiency and FOXO1 activation in muscle is unknown. We generated skeletal muscle‐specific vitamin D receptor (VDR)‐null mice and discovered that these mice developed insulin resistance and glucose intolerance accompanied by increased expression and activity of FOXO1. We also found sustained FOXO1 activation in the skeletal muscle of global VDR‐null mice. Treatment of C2C12 muscle cells with 1,25‐dihydroxyvitamin D (VD3) reduced FOXO1 expression, nuclear translocation, and activity. The VD3‐dependent suppression of FOXO1 activation disappeared by knockdown of VDR, indicating that it is VDR‐dependent. Taken together, these results suggest that FOXO1 is a critical target mediating VDR‐null signaling in skeletal muscle. The novel findings provide the conceptual support that persistent FOXO1 activation may be responsible for insulin resistance and impaired glucose metabolism in vitamin D signaling‐deficient mice, as well as evidence for the utility of vitamin D supplementation for intervention in DM2. © 2015 American Society for Bone and Mineral Research.     

Is there a relationship between vitamin D with insulin resistance and diabetes mellitus?

Available data suggest a possible link between abnormal vitamin D level and abnormal glucose homeostasis, two of the most common chronic medical conditions. Both conditions are associated with inflammation, and the exact mechanism for role of either on the other is not well clear. Literature investigating the link between vitamin D and either pre-diabetic states or diabetes is reviewed. Vitamin D deficiency is detrimental to insulin synthesis and secretion in animal and human studies. In humans, it has been shown by majority of observational studies, that vitamin D is positively correlated with insulin sensitivity and its role is mediated both by direct mechanism through the availability of vitamin D receptors in several tissues and indirectly through the changes in calcium levels. Large number of, but not all, variable samples cross sectional human trials have demonstrated an inverse relation between vitamin D status and impaired glucose tolerance, insulin resistance or diabetes. To compliment this conclusively, evidence from intervention studies is critically warranted before we can frankly state that vitamin D plays a role in diabetes prevention or treatment. Absence of both sizable prospective observational trials utilizing 25(OH)D as the main variable and the non-availability of randomized studies specifically designed to assess the effects of vitamin D on pre-diabetes and diabetes states, are the main obstacles to draw solid and conclusive relationships.     

Insulin and its role in chronic kidney disease

The body’s resistance to the actions of insulin (type II diabetes defect) results in compensatory increased production and secretion by the pancreas and leads to hyperinsulinemia in order to maintain euglycemia. When insulin secretion cannot be increased adequately (type I diabetes defect) to overcome insulin resistance in maintaining glucose homeostasis, hyperglycemia and glucose intolerance ensues. Insulin resistance and glucose intolerance has been well recognized in patients with advanced chronic kidney diseases (CKD). The etiology may involve uremic toxins from protein catabolism, vitamin D deficiency, metabolic acidosis, anemia, poor physical fitness, inflammation, and cachexia. Glucose and insulin abnormalities in nondiabetic CKD patients are implicated in the pathogenesis of hyperlipidemia and may represent important risk factors for accelerated atherosclerosis in these patients. Insulin secretion inadequacy has been associated with growth retardation in adolescents with CKD. Normal adolescents demonstrate an increase in insulin secretion as they go into puberty. It seems that the puberty growth spurt in adolescents both with normal health and renal failure may require increased insulin secretion as one of its hormonal requirements. Finally, insulin resistance has been associated with CKD. Whether insulin resistance is an antecedent of CKD or a consequence of impaired kidney function has been a subject of debate. The goal of this review was to provide an update of the literature on insulin pathophysiology in CKD, current understanding of its mechanisms, and epidemiological association of insulin resistance and CKD. Supported by a Mid-Career Research Development Award K24 DK59574 and U01 DK-03–012 from the National Institute of Health to RHM.     

Conundrum of vitamin D on glucose and fuel homeostasis

As an endocrine hormone, vitamin D plays an important role in bone health and calcium homeostasis. Over the past two decades, the non-calcemic effects of vitamin D were extensively examined. Although the effect of vitamin D on beta cell function were known for some time, the effect of vitamin D on glucose and fuel homeostasis has attracted new interest among researchers. Yet, to date,studies remain inconclusive and controversial, in part, due to a lack of understanding of the threshold effects of vitamin D. In this review, a critical examination of interventional trials of vitamin D in prevention of diabetes is provided. Like use of vitamin D for bone loss, the benefits of vitamin D supplementation in diabetes prevention were observed in vitamin D-deficient subjects with serum 25-hydroxyvitamin D 50 nmol/L(20 ng/mL). The beneficial effect from vitamin D supplementation was not apparent in subjects with serum 25-hydroxyvitamin D 75 nmol/L(30 ng/mL). Furthermore, no benefit was noted in subjects that achieved serum 25-hydroxyvitamin D 100 nmol/L(40 ng/mL).Further studies are required to confirm these observations.     

Pharmacologic adjunctive to insulin therapies in type 1 diabetes:The journey has just begun

Treatment of type 1 diabetes(T1 D) is currently based exclusively on insulin replacement therapy. However, there is a need for better glycemic control, lower hypoglycemia rates, more effective weight management, and further reduction of cardiovascular risk in people with T1 D. In this context, agents from the pharmaceutical quiver of type 2 diabetes are being tested in clinical trials, as adjunctive to insulin therapies for T1 D patients. Despite the limited amount of relevant evidence and the inter-class variability, it can be said that these agents have a role in optimizing metabolic control, assisting weight management and reducing glycemic variability in people with T1 D. Specific safety issues, including the increased risk of hypoglycemia and diabetic ketoacidosis, as well as the effects of these treatments on major cardiovascular outcomes should be further assessed by future studies, before these therapeutic choices become widely available for T1 D management.     

Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease

Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus(DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relation...     

Impact of stopping smoking on metabolic parameters in diabetes mellitus: A scoping review

The purpose of this scoping review is to create a single narrative that describes the impact of smoking cessation on metabolic parameters in people with diabetes. It is generally well accepted that smoking enhances the harmful effects of elevated blood glucose levels, accelerating the vascular damage seen in patients with diabetes. Smoking cessation has clear benefits in terms of reducing cardiovascular morbidity and mortality. However, there is less evidence for the impact of smoking cessation on other diabetes-related complications. Studies in people with diabetes have shown improvement as well as temporary deterioration in glycemic control after ceasing smoking. Only a few studies have described the effect of quitting smoking on insulin resistance and lipid parameters, however, their results have been inconclusive. In this situation, healthcare professionals should not assume that cessation of smoking will improve metabolic parameters in patients with diabetes. It seems they should, first of all, emphasize the prevention of weight gain that may be associated with quitting smoking. The lack of data regarding the metabolic effects of smoking and smoking cessation in diabetes is very disappointing and this area needs to be addressed.     

艾塞那肽在PCOS治疗中的作用及应用前景

艾塞那肽(EX)是一种胰高血糖素样肽-1(GLP-1)类似物,主要用于改善Ⅱ型糖尿病血糖控制不佳及需要减重的患者,是近年来新出现的治疗糖尿病的新型靶点药物。EX具有改善胰岛β细胞的功能、促进葡萄糖依赖性胰岛素的分泌、显著降低餐后血糖、抑制胰高血糖素分泌及减重等众多作用。鉴于多囊卵巢综合征(PCOS)患者常伴有胰岛素抵抗,并且可能合并GLP-1分泌功能受损,目前,学者们开始探索将EX应用于PCOS的治疗。本综述的主要目的是初步阐明EX在PCOS患者治疗中的作用机制,并展望其在生殖内分泌领域的应用前景。     

Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists as a promising strategy for treating diabetes

The maintenance of appropriate glycemic control is important for the prevention of diabetic complications in people with type 2 diabetes(T2D). Numerous oral antidiabetic drugs are now clinically available, but in particular, the introduction of injection regimens using insulin and/or glucagon-like peptide-1 receptor agonist(GLP-1RA)s represents promising step-up options for oral antidiabetic drug treatment. The recently licensed fixed-ratio combination(FRC) products,which comprise basal insulin ...     

Bone health in diabetes and prediabetes

Bone fragility has been recognized as a complication of diabetes, both type 1 diabetes(T1D) and type 2 diabetes(T2D), whereas the relationship between prediabetes and fracture risk is less clear. Fractures can deeply impact a diabetic patient's quality of life. However, the mechanisms underlying bone fragility in diabetes are complex and have not been fully elucidated. Patients with T1D generally exhibit low bone mineral density(BMD), although the relatively small reduction in BMD does not entirely explain the increase in fracture risk. On the contrary, patients with T2D or prediabetes have normal or even higher BMD as compared with healthy subjects. These observations suggest that factors other than bone mass may influence fracture risk. Some of these factors have been identified, including disease duration, poor glycemic control, presence of diabetes complications, and certain antidiabetic drugs. Nevertheless, currently available tools for the prediction of risk inadequately capture diabetic patients at increased risk of fracture. Aim of this review is to provide a comprehensive overview of bone health and the mechanisms responsible for increased susceptibility to fracture across the spectrum of glycemic status, spanning from insulin resistance to overt forms of diabetes. The management of bone fragility in diabetic patient is also discussed.     

Relation of glycated hemoglobin and vitamin D deficiency with erectile dysfunction in patients with type 2 diabetes mellitus

Erectile dysfunction (ED) is seen very often in the men with type 2 diabetes mellitus (DM). Due to the ability of vitamin D to reduce endothelial damage and oxidative stress, its role in preventing cardiovascular risk has been demonstrated in some studies. Since ED and cardiovascular disease have common pathogenic mechanisms, many studies have evaluated a possible relationship between vitamin D deficiency and ED. Total 120 patients with type 2 diabetes mellitus were evaluated in this study. Vitamin D and HbA1c values were statistically compared according to International Index of Erectile Dysfunction (IIEF-5) scores. 23.3% of 120 patients had mild, 38.3% had mild to moderate, 21.7% had moderate and 16.7% had severe ED. There was statistically difference in vitamin D levels of the patients according to IIEF-5 scores. Also, significant difference was found in HbA1c levels between the patients with severe ED and other groups. Cut-off point for vitamin D and HbA1c were determined according to IIEF-5 score in patients who were divided in to two groups (14.41 and 11.1). A statistically significant correlation was found between both cut-off points and IIEF-5 scores. Our study shows that patients with ED have a vitamin D deficiency and a poor glycemic control.     

Changing trends in management of gestational diabetes mellitus

Gestational diabetes mellitus(GDM)is on the rise globally.In view of the increasing prevalence of GDM and fetal and neonatal complications associated with it,there is a splurge of research in this field and management of GDM is undergoing a sea change.Trends are changing in prevention,screening,diagnosis,treatment and future follow up.There is emerging evidence regarding use of moderate exercise,probiotics and vitamin D in the prevention of GDM.Regarding treatment,newer insulin analogs like aspart,lispro and detemir are associated with better glycemic control than older insulins.Continuous glucose monitoring systems and continuous subcutaneous insulin systems may play a role in those who require higher doses of insulin for sugar control.Evidence exists that favors metformin as a safer alternative to insulin in view of good glycemic control and better perinatal outcomes.As the risk of developing GDM in subsequent pregnancies and also the risk of overt diabetes in later life is high,regular assessment of these women is required in future.Lifestyle interventions or metformin should be offered to women with a history of GDM who develop pre-diabetes.Further studies are required in the field of prevention of GDM for optimizing obstetric outcome.     

The effects of vitamin D treatment on glycemic control,serum lipid profiles,and C-reactive protein in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials

Purpose

Insulin resistance, dyslipidemia and increased systemic inflammation are important risk factors for chronic kidney disease (CKD). Hence, vitamin D administration might be an appropriate approach to decrease the complications of CKD. Randomized controlled trials assessing the effects of vitamin D supplementation or treatment on glycemic control, lipid profiles, and C-reactive protein (CRP) among patients with CKD were included.

Methods

Two independent authors systematically searched online databases including EMBASE, Scopus, PubMed, Cochrane Library, and Web of Science in November 2018 with no time restriction. Cochrane Collaboration risk of bias tool was applied to assess the methodological quality of included trials. Between-study heterogeneity was estimated using the Cochran’s Q test and I-square (I²) statistic. Data were pooled using a random-effects model and weighted mean difference (WMD) was considered as the overall effect size.

Results

Of the 1358 citations identified from searches, 17 full-text articles were reviewed. Pooling findings from five studies revealed a significant reduction in fasting glucose (WMD:???18.87; 95% CI:???23.16,???14.58) and in homeostatic model assessment of insulin resistance (HOMA-IR) through three studies (WMD:???2.30; 95% CI:???2.88,???1.72) following the administration of vitamin D. In addition, pooled analysis revealed a significant reduction in triglycerides (WMD:???32.52; 95% CI:???57.57,???7.47) through six studies and in cholesterol concentrations (WMD:???7.93; 95% CI:???13.03,???2.83) through five studies, following vitamin D supplementation or treatment, while there was no effect on insulin, HbA1c, LDL and HDL cholesterol, and CRP levels.

Conclusions

This meta-analysis demonstrated the beneficial effects of vitamin D supplementation or treatment on improving fasting glucose, HOMA-IR, triglycerides and cholesterol levels among patients with CKD, though it did not influence insulin, HbA1c, LDL and HDL cholesterol, and CRP levels.

     

A fairy tale of modern insulin therapy in type 1 diabetes

In type 1 diabetes, flexible, intensive insulin management improves not only glycemic control but also dietary freedom and treatment satisfaction. Such flexibility has been made possible with the new insulin analogues (as part of a basal-bolus regime) and is now gaining wide applicability, especially among children and adolescents. This approach requires appropriate individualized patient education. Especially for adolescents, the clinician should be able to guarantee insightful participation in direct response to their attitudes, wishes and needs. This patient-and-doctor collaboration is an ever-challenging duty and has the potential to change the future of the individual diabetic patient.     

Synthesis rate of muscle proteins,muscle functions,and amino acid kinetics in type 2 diabetes

Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO(2max). We investigated the effect of 11 days of intensive insulin treatment (T(2)D+) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T(2)D-) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T(2)D-. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.     

Vitamin D, insulin resistance, and renal disease

Chonchol and Scragg report the results of a population study on levels of 25-hydroxyvitamin D in patients with renal dysfunction. They demonstrate that these patients do not show vitamin D deficiency unless renal function is severely affected (GFR<29 mL/min/1.73m2), while vitamin D and renal function loss are independently associated with insulin resistance. These data provide more solid evidence than previous available studies on small patient groups, and pose new questions about the mechanisms responsible for progressive renal disease as well as potential effects of vitamin D supplementation.