Metabolic Derangements In Type Research Articles

Gut microbiota compositions and metabolic functions in type 2 diabetes differ with glycemic durability to metformin monotherapy

AimsThe metabolic derangements in type 2 diabetes have been attributed to compositional changes in the gut microbiota. Metformin, the first-line treatment for type 2 diabetes, has been found to modulate the gut microbiota. However, no literature has reported the associations between the composition of the gut microbiota and glycemic durability to metformin monotherapy. MethodsA total of 375 patients with type 2 diabetes were recruited, among which 14 and 11 patients were eligible as the metformin durable group and nondurable group, respectively. Fecal samples were collected to analyze the gut microbiota by Illumina sequencing of the 16S rRNA gene, and PICRUSt2 was adopted to infer microbial functional differences. ResultsAlthough the two groups had similar biochemical profiles and microbial metabolites, the pattern of microbiota clustering was different. The intra-group diversity was significantly reduced in the durable group. For the microbial metabolic pathways, the biosynthesis of thiamine and lipopolysaccharide was dominant in the durable group. ConclusionsThere were different compositions of gut microbiota with unique microbial metabolic pathways between type 2 diabetes with and without glycemic durability to metformin monotherapy. Microbial salvage by increasing thiamine biosynthesis might be beneficial for the metformin durable group to maintain optimal glycemic control.

Plasma Cathepsin D Activity Rather Than Levels Correlates With Metabolic Parameters of Type 2 Diabetes in Male Individuals.

ObjectiveType 2 diabetes mellitus is a metabolic disorder characterized by insulin resistance. Previous studies in patients demonstrated that plasma levels of cathepsin D (CTSD), which is optimally active in the acidic environment of lysosomes, correlate with insulin resistance. As plasma pH is slightly reduced in type 2 diabetic patients and we have previously shown that plasma CTSD activity is causally linked to insulin levels in vivo, it is likely that the activity of CTSD in plasma will be increased in type 2 diabetes compared to healthy individuals. However, so far the interaction between CTSD activity and levels to postprandial metabolic derangements in type 2 diabetes is not known.MethodsEighteen type 2 diabetes and 16 age-matched healthy males were given 2 consecutive standardized mixed meals, after which blood samples were collected. Plasma metabolic parameters as well as CTSD levels and activity were measured, and changes in plasma pH was assessed.ResultsIn line with the elevation of plasma free fatty acids (FFA) levels in male type 2 diabetics patients, plasma pH in type 2 diabetic individuals was decreased compared to male healthy individuals. While plasma CTSD levels were similar, plasma CTSD activity was increased in male type 2 diabetic compared to male healthy individuals. Besides, plasma CTSD activity rather than levels significantly correlated with indicators of type 2 diabetes (HbA1c, HOMA-IR and glucose). Furthermore, FFA was also independently associated with plasma CTSD activity (standardized β = 0.493, p = 0.007).ConclusionsDespite similar plasma CTSD levels, type 2 diabetic male individuals showed increased plasma CTSD activity compared to healthy males, which was independently linked to plasma FFA levels. Our data therefore point toward plasma CTSD as a metabolic regulator in male type 2 diabetes.

1173-P: Therapeutic Response to Metformin Monotherapy in Type 2 Diabetes Is Associated with Butyrate-Producing Gut Microbiota

Type 2 diabetes is the fifth leading cause of death in Taiwan. The metabolic derangements in type 2 diabetes have been attributed to the compositional changes of the gut microbiota. Metformin, as the first-line treatment for type 2 diabetes, has been found to exert its antidiabetic actions through modulations of the gut microbiota. However, to our knowledge, no literature reported the associations between the therapeutic response to metformin monotherapy and the compositions of the gut microbiota. Thus, we hypothesized that the compositions of gut microbiota differ in type 2 diabetes with failure and success of metformin monotherapy. We had recruited 381 type 2 diabetes diagnosed for more than two years in a university hospital. Then based on medical records, we identified 12 subjects as the metformin-failure group and 14 as the metformin-success group, who maintained HbA1C>7% with not only metformin or with metformin monotherapy, respectively. We collected the biochemical data and analyzed the gut microbiota by Illumina sequencing of 16S rRNA gene. The result showed that while the two groups having similar clinical characteristics, the gut microbiota were significantly different by principal coordinates analysis. In addition, the metformin-success group had decreased richness and evenness. Furthermore, butyrate-producing gut microbiota including Butyrivibrio and Blautia producta increased in the metformin-success group. The short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, are produced by gut microbiota. The imbalance in the ratio of the SCFAs, such as decrease in butyrate and increase in acetate, leads to metabolic derangements in type 2 diabetes. Our finding showed that the metformin-success group were associated with butyrate-producing gut microbiota. In conclusion, the gut microbiota that can reverse the imbalance of SCFAs might be the key for diabetes to have sustained metabolic benefits with metformin monotherapy. Disclosure W. Hung: None. W. Hung: None. Funding Kaohsiung Medical University

Association of Sympathovagal Imbalance With Cognitive Impairment in Type 2 Diabetes in Adults.

Sympathovagal imbalance (SVI) has been reported to be associated with metabolic derangements in type 2 diabetes. We investigated the association of SVI with cognitive impairment in patients with type 2 diabetes. Patients with a new diagnosis of type 2 diabetes (n=43) and age-matched healthy control subjects (n=43) were recruited for the study. Body mass index and blood pressure measurements were recorded. SVI was assessed by spectral analysis of heart rate variability (HRV), and cognitive function was assessed by recording the positive wave that appears in 300 milliseconds from application of stimulus in event-related potential tracing (P300). Insulin resistance was determined by the homeostatic model assessment of insulin resistance (HOMA-IR) formula using blood glucose and insulin data, and oxidative stress was assessed by estimation of malondialdehyde. Association of various factors with cognitive impairment was evaluated by Pearson correlation analysis, and independent contributions of these factors to cognitive impairment were assessed by multiple regression analysis. P300 latency was significantly prolonged in the diabetes group compared with the control group. Ratio of low-frequency to high-frequency power (LF-HF ratio) of HRV, the marker of SVI was found to be significantly correlated and linked with P300. Malondialdehyde and HOMA-IR were correlated with LF-HF ratio. Treatment-naïve patients with type 2 diabetes have SVI and considerable cognitive impairment. Insulin resistance and oxidative stress contribute to cognitive impairment, and SVI could be the physiologic link to cognitive impairment in treatment-naïve patients with type 2 diabetes.

Proteasome inhibition in skeletal muscle cells unmasks metabolic derangements in type 2 diabetes.

Two-dimensional difference gel electrophoresis (2-D DIGE)-based proteome analysis has revealed intrinsic insulin resistance in myotubes derived from type 2 diabetic patients. Using 2-D DIGE-based proteome analysis, we identified a subset of insulin-resistant proteins involved in protein turnover in skeletal muscle of type 2 diabetic patients, suggesting aberrant regulation of the protein homeostasis maintenance system underlying metabolic disease. We then validated the role of the ubiquitin-proteasome system (UPS) in myotubes to investigate whether impaired proteasome function may lead to metabolic arrest or insulin resistance. Myotubes derived from muscle biopsies obtained from people with normal glucose tolerance (NGT) or type 2 diabetes were exposed to the proteasome inhibitor bortezomib (BZ; Velcade) without or with insulin. BZ exposure increased protein carbonylation and lactate production yet impaired protein synthesis and UPS function in myotubes from type 2 diabetic patients, marking the existence of an insulin-resistant signature that was retained in cultured myotubes. In conclusion, BZ treatment further exacerbates insulin resistance and unmasks intrinsic features of metabolic disease in myotubes derived from type 2 diabetic patients. Our results highlight the existence of a confounding inherent abnormality in cellular protein dynamics in metabolic disease, which is uncovered through concurrent inhibition of the proteasome system.

Levo-carnitine reduces oxidative stress and improves contractile functions of fast muscles in type 2 diabetic rats.

Metabolic derangements in type 2 diabetes mellitus (T2DM) are likely to affect skeletal muscle contractile functions adversely. Levo-carnitine improves muscle contractile functions in healthy humans and rats and corrects metabolic derangements in T2DM. Therefore, it is likely to improve muscle contractile functions in T2DM as well. This study was designed to determine the effect of levo-carnitine on serum levo-carnitine levels, oxidative stress and contractile parameters of fast muscle in T2DM. Ninety Sprague-Dawley rats were randomly divided into three equal groups. Healthy rats served as the controls, while T2DM was induced in diabetic and carnitine groups. The carnitine group was administered levo-carnitine 200 mg/kg/day intraperitoneally for 6 days. At 28th day, extensor digitorum longus muscles were removed and their functions were assessed using iWorx data acquisition unit (AHK/214). Blood obtained by intra-cardiac sampling at 28th day was used for estimation of serum malondialdehyde (MDA) and levo-carnitine levels. Maximum isometric twitch tension, time-to-peak twitch tension and time-to-relax to 50% of the peak twitch tension were not significantly different amongst the groups. Carnitine group showed significant improvement in maximum fused tetanic tension, maximum fused tetanic tension after fatigue protocol and recovery from fatigue after 5 minutes of rest period compared to the diabetic group. Serum MDA levels were reduced, while serum levo-carnitine levels were elevated significantly in carnitine group as compared to the diabetic group. Levo-carnitine supplementation increases serum levo-carnitine levels which decreases oxidative stress. This action improves contractile force but delays fatigue in fast muscles of diabetic rats.

Metformin and Cancer in Type 2 Diabetes

Metformin and Cancer in Type 2 Diabetes

Metabolic Effects of Honey in Type 1 Diabetes Mellitus: A Randomized Crossover Pilot Study

The aim of this study was to evaluate the metabolic effects of 12-week honey consumption on patients suffering from type 1 diabetes mellitus (DM). This was a randomized crossover clinical trial done in the National Institute for Diabetes and Endocrinology, Cairo, Egypt. Twenty patients of both sexes aged 4-18 years with type 1 DM and HbA1C<10% participated in the study. They were randomized into two equal groups (intervention to control and control to intervention). The dietary intervention was 12-week honey consumption in a dose of 0.5 mL/kg body weight per day. The main outcome measures were serum glucose, lipids, and C-peptide, and anthropometric measurements. None of participants were lost in follow-up. The intervention resulted in significant decreases in subscapular skin fold thickness (SSFT; P=.002), fasting serum glucose (FSG; P=.001), total cholesterol (P=.0001), serum triglycerides (TG; P=.0001), and low-density lipoprotein (P=.0009), and significant increases in fasting C-peptide (FCP; P=.0004) and 2-h postprandial C-peptide (PCP; P=.002). As possible long-term effects of honey after its withdrawal, statistically significant reductions in midarm circumference (P=.000), triceps skin fold thickness (P=.006), SSFT (P=.003), FSG (P=.005), 2-h postprandial serum glucose (P=.000), TG (P=.003), and HbA1C (P=.043), and significant increases in FCP (P=.002) and PCP (P=.003) were observed. This small clinical trial suggests that long-term consumption of honey might have positive effects on the metabolic derangements of type 1 DM.

Acute blood glucose fluctuations can decrease blood glutathione and adiponectin levels in patients with type 2 diabetes

IntroductionGlutathione appears to have apparent antioxidant activity to counter regulate hyperglycemia induced oxidative stress. Adiponectin also plays a role in the suppression of the metabolic derangements in type 2 diabetes mellitus (DM). The aim of this study was to determine whether blood glucose fluctuations can alter blood levels of glutathione and adiponectin. MethodsWe enrolled 34 patients with type 2 DM. As a measure of short-term glycemic variability, the mean amplitude of glycemic excursions (MAGE) was computed from a continuous glucose monitor system (CGMS), and data were recorded over 72h. For long-term glycemic variability, we calculated the standard deviation (SD) of HbA1c over a 2-year period. Glutathione and adiponectin levels were measured after completing the 72-h CGMS data collection. ResultsThe blood levels of glutathione were significantly and negatively correlated with MAGE (r=−0.543; P<0.001), but not with HbA1c and SD of HbA1c. Adiponectin levels were also significantly and negatively correlated with MAGE and SD of HbA1c (r=−0.64 and r=−0.55, respectively; P<0.001). Using generalized estimating equations, multivariate regression analysis revealed that MAGE is an independent predictor of serum levels of adiponectin (P=0.002) and glutathione (P=0.004). ConclusionsWe found strong associations between acute blood glucose variability, glutathione, and adiponectin in type 2 diabetic patients treated with oral hypoglycemic agent therapy.

Levo-carnitine supplementation normalizes skeletal muscle functions in type 2 diabetic rats

Levo-carnitine is known to improve skeletal muscle contractile functions in healthy humans and rats. It has also been claimed to correct metabolic derangements in type 2 diabetes mellitus (T2DM). This randomized control trial was designed to determine the effect of levo-carnitine on isometric contraction, force frequency relationship and fatigue of skeletal muscles along with oxidative stress in T2DM. Sprague-dawley rats (n=90) were randomly divided in three equal groups. Control group remained healthy while T2DM was induced in the diabetic and carnitine groups. Then, carnitine group was administered levo-carnitine 200mg/kg/day intraperitonealy for 6 days. At 28th day, extensor digitorum longus (EDL) muscles were removed and their functions were assessed using iWorx data acquisition unit (AHK/214). Blood obtained by intra-cardiac sampling at 28th day was used for estimation of serum malondialdehyde (MDA) levels. Regarding muscle parameters, no significant difference was found in maximum isometric twitch tension, time-to-peak twitch tension and time-to-relax to 50% of the peak twitch tension amongst the three groups. However, carnitine group showed significant improvement in maximum fused tetanic tension, maximum fused tetanic tension after fatigue protocol and recovery from fatigue after 5 minutes of rest period when compared with diabetic group. Serum MDA levels were reduced in carnitine group as compared to the diabetic group. These findings suggest that levo-carnitine supplementation reduces oxidative stress, improves work capacity and delays fatigue in T2DM.

Effects of glycemic control and other determinants on vascular disease in type 2 diabetes

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes, with more than 77,000 deaths each year. The risk remains high despite normalization of well-known cardiovascular risk factors, and the impact of glycemic control on risk reduction remains controversial. Deleterious changes in fibrinolysis, platelet function, and coagulation secondary to insulin resistance and/or the metabolic derangements of type 2 diabetes have emerged as likely mechanisms underlying increased cardiovascular risk. Plasminogen activator inhibitor–1 (PAI-1) is an inhibitor of the fibrinolytic system. Thus, elevated concentrations of PAI-1 promote persistence of clots. Concentrations of PAI-1 are elevated in the blood and vessel walls of patients with type 2 diabetes or other insulin-resistant states. We have hypothesized that increased PAI-1 can create conditions favorable to the evolution of unstable, lipid-laden atherosclerotic coronary plaques, thereby rendering patients with diabetes highly susceptible to rupture of vulnerable plaques and acute coronary syndromes. Therapeutic interventions that may alter this evolution by reducing concentrations of PAI-1 or correct metabolic derangements that promote it are being studied. Antiplatelet therapy has been directed at the increased platelet reactivity characteristic of patients with diabetes. Its use has reduced complications after percutaneous coronary intervention following the onset of unstable angina. Amelioration of diabetic cardiomyopathy by correction of impaired myocardial energy metabolism and limiting the accumulation of advanced glycation end products is being evaluated as well.

Mechanisms in the development of type 2 diabetes mellitus.

The leading cause of death among patients with type 2 diabetes mellitus (DM) is cardiovascular disease, with 75% of these deaths attributed to coronary heart disease. Over the previous two decades the pathophysiological basis of type 2 DM has been extensively investigated. Although many of the underlying molecular mechanisms involved in the development of this disorder remain to be explained, it is clear that type 2 DM is a complex medical disorder characterized by insulin resistance and defects in insulin secretion. The process through which the metabolic derangements of type 2 DM accelerate the development of cardiovascular disease in type 2 DM has yet to be determined and remains an area of intense investigation, focusing on hyperglycemia and insulin resistance as major underlying contributors. This article explores current information related to the pathophysiology of type 2 DM alone and its relationship to the development to cardiovascular disease.