Uncontrolled hypertension in patients with type 2 diabetes: What are the correlates?

Suboptimal blood pressure (BP) control in patients with type 2 diabetes is associated with adverse micro‐ and macrovascular complications. This study aimed to investigate the predictors of uncontrolled hypertension in an Iranian population with type 2 diabetes. This is a cross‐sectional study of 2612 patients with type 2 diabetes, including 944 patients with hypertension. Controlled and uncontrolled hypertension were assessed. Multivariate logistic regression modeling was used to determined independent predictors of uncontrolled hypertension. Of 2612 patients with type 2 diabetes, 944 (36.1%) patients had hypertension. Of all patients with hypertension, 580 (61.4%) were still on monotherapy. Uncontrolled hypertension was detected in 536 participants (56.8%). Patients with uncontrolled hypertension had significantly higher body mass index (BMI) (29.8±4.8 vs. 28.6±4.6), waist circumference (99.11±10.95 vs. 96.68±10.92), pulse pressure (67.3±17.3 vs. 48.4±10.7), total cholesterol (177.1±45.5 vs. 164.3±40.5), non‐HDL cholesterol (133.0±43.5 vs. 120.1±38.7), triglycerides (175.7±80.3 vs. 157.4±76.7), and Atherogenic Index of Plasma (AIP) (0.57±0.23 vs. 0.52±0.24) (p < .05 for all of them) compared to patients with controlled hypertension. Multivariate logistic regression analysis revealed that uncontrolled hypertension was significantly associated with BMI (p = .001), pulse pressure (p = .001), total cholesterol (p = .006), and non‐HDL cholesterol (p = .009). In patients with triglycerides levels > 200 mg/dl non‐HDL cholesterol had a significant correlation with uncontrolled hypertension (OR = 4.635, CI95%:1.781–12.064, p = .002). In conclusion, BMI, pulse pressure, total cholesterol, and non‐HDL cholesterol are significant predictors of uncontrolled hypertension in patients with type 2 diabetes. Also, ineffective monotherapy, medical inertia and patients’ non‐compliance were other contributors to the uncontrolled hypertension.     

Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes

Aim: To study the effect of dipeptidyl peptidase‐4 (DPP‐4) inhibition with saxagliptin on β‐cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Methods: Patients in this randomized, parallel‐group, double‐blind, placebo‐controlled study were drug‐naÏve, aged 43–69 years, with baseline haemoglobin A1c (HbA1c) 5.9–8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0–180 min, fasting state), and intravenous‐oral hyperglycaemic clamp (180–480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C‐peptide deconvolution. Results: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference ?21.8% vs. placebo, p = 0.03). Conclusions: DPP‐4 inhibition with saxagliptin improves pancreatic β‐cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP‐4 inhibition on the β‐cell is warranted.     

Effect of initial combination therapy with sitagliptin and metformin on β-cell function in patients with type 2 diabetes

Aim: To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of β‐cell function in patients with type 2 diabetes. Methods: The data used in the present analyses are from a 104‐week study, which included a 24‐week, placebo‐ and active controlled phase followed by a 30‐week, active controlled, continuation phase and an additional 50‐week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. β‐cell responsivity was assessed with the C‐peptide minimal model. The static component (Φ_s) estimates the rate of insulin secretion related to above‐basal glucose concentration. The dynamic component (Φ_d) is related to the rate of change in glucose. The total index (Φ_total) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ_s and Φ_d. Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ_total and ISI. Results: At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ_s, Φ_total and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ_s increased from baseline by 137 and 177% in the low‐ and high‐dose combination groups and by 85, 54, 73 and ?9% in the high‐dose metformin, low‐dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in β‐cell function relative to their respective monotherapy groups. Conclusions: After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved β‐cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in β‐cell function were found with treatments for up to 2 years.     

Association of plasma soluble α-klotho with pro-endothelin-1 in patients with type 2 diabetes

Objectives

To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM).

Subjects and methods

In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively.

Results

Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8 ± 148.1 vs. 494.6 ± 134.3 pg/ml, p = 0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho = −0.410, p < 0.0001) but not in non-diabetic controls (Rho = 0.091, p = 0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure.

Conclusions

Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM.     

Glucose regulation of β-cell stress in type 2 diabetes

In type 2 diabetes, the β-cell is exposed to chronic hyperglycaemia, which increases its metabolic activity, with excess generation of reactive oxygen species (ROS) as a consequence. ROS accumulation induces both oxidative and endoplasmic reticulum (ER) stress, which may lead to β-cell dysfunction and apoptosis. Recent data suggest that oxidative and ER stress are interconnected, although the mechanisms involved in nutrient regulation of the different stress pathways are dissimilar. Several components of the oxidative and ER stress machineries have important roles in the physiological response to glucose and are thus necessary for normal β-cell function. Glucose stimulates signalling pathways that provide crucial messages for β-cell adaptation to metabolic stress; however, the same pathways may eventually lead to apoptosis. Dynamic, temporally fluctuating activation of stress signalling is probably required for the maintenance of β-cell survival, whereas its persistent activation results in β-cell dysfunction and apoptosis. Thus, stress signalling is a 'double-edged sword' that may promote adaptation or apoptosis according to the balance between the divergent outputs of the various pathways. Developing new strategies for β-cell protection based on inhibition of oxidative and/or ER stress requires comprehensive understanding of the switch from β-cell adaptation to β-cell apoptosis under conditions of metabolic stress, such as occurs under hyperglycaemic conditions.     

Cause-specific mortality in Scottish patients with colorectal cancer with and without type 2 diabetes (2000–2007)

Aims/hypothesis

The objective of this study was to use Scottish national data to assess the influence of type 2 diabetes on (1) survival (overall and cause-specific) in multiple time intervals after diagnosis of colorectal cancer and (2) cause of death.

Methods

Data from the Scottish Cancer Registry were linked to data from a population-based national diabetes register. All people in Scotland diagnosed with non-metastatic cancer of the colon or rectum in 2000–2007 were included. The effect of pre-existing type 2 diabetes on survival over four discrete time intervals (<1, 1–2, 3–5 and >5 years) after cancer diagnosis was assessed by Cox regression. Cumulative incidence functions were calculated representing the respective probabilities of death from the competing causes of colorectal cancer, cardiovascular disease, other cancers and any other cause.

Results

Data were available for 19,505 people with colon or rectal cancer (1,957 with pre-existing diabetes). Cause-specific mortality analyses identified a stronger association between diabetes and cardiovascular disease mortality than that between diabetes and cancer mortality. Beyond 5 years after colon cancer diagnosis, diabetes was associated with a detrimental effect on all-cause mortality after adjustment for age, socioeconomic status and cancer stage (HR [95% CI]: 1.57 [1.19, 2.06] in men; 1.84 [1.36, 2.50] in women). For patients with rectal cancer, diabetes was not associated with differential survival in any time interval.

Conclusions/interpretation

Poorer survival observed for colon cancer associated with type 2 diabetes in Scotland may be explained by higher mortality from causes other than cancer.     

Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes

This 24-week, double-blind, randomized, multicenter, placebo-controlled, parallel-group study performed in 354 drug-na?ve patients with type 2 diabetes (T2DM) assessed efficacy and tolerability of vildagliptin (50mg qd, 50mg bid, or 100mg qd). The primary assessment was change from baseline to endpoint in hemoglobin A1c (A1C), comparing vildagliptin to placebo by ANCOVA. Baseline A1C averaged 8.4% and the between-treatment difference (vildagliptin-placebo) in adjusted mean change (AMDelta) in A1C was -0.5+/-0.2% (P=0.011), -0.7+/-0.2% (P<0.001), and -0.9+/-0.2% (P<0.001) in patients receiving vildagliptin 50 mg qd, 50 mg bid, or 100 mg qd, respectively. Baseline FPG averaged 10.5 mmol/L; the between-treatment difference in AMDelta FPG was -0.6+/-0.4 mmol/L in patients receiving vildagliptin 50mg qd and -1.3+/-0.4 mmol/L (P=0.001) in both groups receiving 100mg daily. Relative to baseline, body weight did not change significantly in any of the three vildagliptin groups and decreased by 1.4+/-0.4 kg in the placebo group. Adverse events (AEs) occurred with similar frequency in each group: 55.8%, 59.3%, 59.3%, and 57.6% of patients receiving vildagliptin 50 mg qd, 50 mg bid, 100 mg qd, or placebo, respectively, experienced an AE. No confirmed hypoglycemia was reported. Conclusion: Vildagliptin is effective and well-tolerated in drug-na?ve patients with T2DM and 100 mg vildagliptin provides similar clinical benefit whether given as single or in divided doses.     

The type of stoma matters—morbidity in patients with obstructing colorectal cancer

Purpose

A loop colostomy may reduce the risk of severe intraabdominal complications in patients with obstructing colorectal cancer compared to an end colostomy. The aim of this study was to relate complications to the type of stoma, and a secondary aim was to evaluate whether the type of colostomy had an impact on time until oncological/surgical treatment.

Methods

All patients who underwent surgery and received a deviating colostomy due to obstructing colorectal cancer between January 2011 and December 2015 in five Swedish hospitals in Region Västra Götaland were included (n?=?289). Patient charts were reviewed retrospectively. Patients alive in the end of 2016 were contacted and were sent a questionnaire including questions about stoma function and health-related quality of life.

Results

Some 289 patients were included; 147 received an end colostomy and 140 a loop colostomy. Two patients were excluded from the analysis due to missing data. There was no difference in complications at 90 days between the two groups, 44% (end colostomy) and 54% (loop colostomy) (odds ratio: 0.83 (95% CI: 0.49; 1.41). Time to start of treatment was similar in both groups. Patients with a loop colostomy had significantly higher stoma-related morbidity with retraction, prolapse, leakage and bandaging problems. No differences in quality of life were found.

Conclusion

The hypothesis that a loop colostomy reduced complications could not be confirmed. An end colostomy should be the first choice in these patients particularly in patients who will have their colostomy for the remainder of their life to reduce stoma-related symptoms.

     

Can exercise minimize postprandial oxidative stress in patients with type 2 diabetes?

It has recently been estimated by the American Diabetes Association that 21 million Americans, or about 7% of the U.S. population, have diabetes, while an additional 54 million Americans have pre-diabetes. The onset and progression of these disorders and related complications are linked to impairments in glucose and lipid metabolism, both of which are associated with increased production of reactive oxygen and nitrogen species (RONS). Increased RONS production coupled with impaired antioxidant defense (a common finding among patients with diabetes) promotes oxidation of specific biomolecules (lipid, protein, DNA), which can lead to an exacerbation of diabetic complications. While bloodborne variables related to these disorders have traditionally been measured in a fasted state, increasing evidence suggests that measurement of postprandial glycemia, lipemia, and oxidative stress may provide more important clinical information concerning an individual's susceptibility to diabetes onset and disease progression. While drugs to treat hyperglycemia and hyperlipidemia have been reported in some studies to promote favorable outcomes related to attenuating the postprandial rise in blood glucose and triglycerides, one non-pharmaceutical approach which may have promise is the performance of regular exercise. Both acute and chronic exercise may aid in attenuating postprandial oxidative stress in three distinct ways. First, exercise stimulates an increase in endogenous antioxidant enzyme activity. Second, exercise improves blood glucose clearance via enhanced GLUT 4 translocation and protein content, as well as enhanced insulin-insulin receptor binding and post-receptor signaling. Third, exercise improves blood triglyceride clearance via a reduced chylomicron-triglyceride half-life and enhanced lipoprotein lipase activity. In this article we provide evidence for the potential role of exercise in modulating postprandial oxidative stress in diabetic and pre-diabetic individuals. It is certainly possible that exercise may prove beneficial in this regard. If so, and in accordance with the recent joint initiative of the American College of Sports Medicine and the American Medical Association, exercise may be viewed as "medicine" for individuals who are at increased risk for postprandial oxidative stress.     

The role of autophagy in β-cell lipotoxicity and type 2 diabetes

Autophagy, a ubiquitous catabolic pathway involved in both cell survival and cell death, has been implicated in many age-associated diseases. Recent findings have shown autophagy to be crucial for proper insulin secretion and β-cell viability. Transgenic mice lacking autophagy in their β-cells showed decreased β-cell mass and suppressed glucose-stimulated insulin secretion. Several studies showed that stress can stimulate autophagy in β-cells: the number of autophagosomes is increased in different in vivo models for diabetes, such as db/db mice, mice fed high-fat diet, pdx-1 knockout mice, as well as in in vitro models of glucotoxicity and lipotoxicity. Pharmacological and molecular inhibition of autophagy increases the susceptibility to cell stress, suggesting that autophagy protects against diabetes-relevant stresses. Recent findings, however, question these conclusions. Pancreases of diabetics and β-cells exposed to fatty acids show accumulation of abnormal autophagosome morphology and suppression of lysosomal gene expression suggesting impairment in autophagic turnover. In this review we attempt to give an overview of the data generated by others and by us in view of the possible role of autophagy in diabetes, a role which depending on the conditions, could be beneficial or detrimental in coping with stress.     

Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with β-catenin

Backgrounds and aims  

Lgr5 is a member of the G protein receptor super-family and was shown recently to be a stem cell marker for cells with intestinal differentiation. Its over-expression has been demonstrated in hepatocellular, basal cell carcinoma, and ovarian cancers but the underlying mechanisms are poorly understood. The aim of this study was to investigate if Lgr5 over-expression was correlated with human colorectal carcinogenesis and its potential correlation with β-catenin.     

Altered distribution of β-catenin and prognostic roles in colorectal carcinogenesis

Objective. Although β-catenin cytoplasmic stabilization and nuclear translocation play a key role in initiation of colorectal cancer (CRC), the mechanisms are far from clear. The aim of this study was to investigate the relation of expressions of cyclooxygenase (COX)-2 and E-cadherin, and the β-catenin gene exon 3 mutation to the altered distribution of β-catenin, and their roles in CRC progression and prognosis. Material and methods. Expressions of β-catenin, COX-2 and E-cadherin in 96 tissue specimens were detected by immunohistochemistry, and mutation of β-catenin gene exon 3 was screened by polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC). Results. Cytoplasmic/nuclear expression of β-catenin and reduced membranous expression of E-cadherin were associated, respectively, with the earlier and later stages of sequential colorectal carcinogenesis (p<0.05). The altered distribution of β-catenin was significantly associated with both high Dukes’ stages and poor differentiation of CRC (p<0.05). It also had a parallel relationship with COX-2 overexpression (p<0.05, Spearman's rank analysis), but not with reduced E-cadherin expression. Kaplan-Meier analysis showed a significantly worse survival rate for CRC patients with altered expression of β-catenin (p<0.05, log-rank test). Nevertheless, we failed to find any exon 3 mutation of β-catenin gene in all 60 cases of CRC. Conclusions. Altered distribution of β-catenin occurs in the early stage of colorectal carcinogenesis and has a parallel relationship with COX-2 overexpression. It may serve as a potential marker for the progression and prognosis of CRC. The exon 3 mutation did not appear contributive to the abnormal expression of β-catenin in CRCs in a Chinese population.     

Performance of the revised ‘175’ Modification of Diet in Renal Disease equation in patients with type 2 diabetes

AIMS/HYPOTHESIS: Estimation of GFR (eGFR) is recommended for the assessment of kidney function in all patients with diabetes. We studied performance of the traditional '186' Modification of Diet in Renal Disease (MDRD) equation, and the 2005 revised '175' MDRD equation in patients with type 2 diabetes. METHODS: Two hundred and ninety-three mainly normoalbuminuric (267/293) patients were recruited. Patients were classified as having mild renal impairment (group 1, GFR <90 ml min(-1) 1.73 m(-2)) or normal renal function (group 2, GFR >or=90 ml min(-1) 1.73 m(-2)). eGFR was calculated by the traditional 186 MDRD equation using traditional creatinine values and the revised 175 MDRD equation using isotope dilution mass spectrometry-standardised creatinine values. Isotopic GFR was measured by the four-sample plasma clearance of (51)Cr-EDTA. RESULTS: For patients in group 1, mean +/- SD isotopic (51)Cr-EDTA GFR (iGFR) was 83.8 +/- 4.3 ml min(-1) 1.73 m(-2), and eGFR was 73.2 +/- 11.9 and 75.8 +/- 13.7 ml min(-1) 1.73 m(-2) using the 186 and 175 MDRD equations, respectively. Method bias was -10.6 with the 186 MDRD and -7.9 ml min(-1) 1.73 m(-2) (p < 0.05) with the 175 MDRD equation. In group 2, iGFR was 119.4 +/- 20.2 ml min(-1) 1.73 m(-2), and eGFR was 92.3 +/- 18.6 and 97.5 +/- 21.6 ml min(-1) 1.73 m(-2) using the 186 and 175 MDRD equations, respectively. Method bias was -27.1 with the 186 MDRD equation and -21.9 ml min(-1) 1.73 m(-2) (p < 0.05) with the 175 MDRD equation. CONCLUSIONS/INTERPRETATION: In patients newly diagnosed with type 2 diabetes, the revised 175 MDRD equation was less biased than the traditional 186 MDRD equation. Despite a continued tendency to underestimate isotopically measured GFR, use of standardised creatinine values is a positive step towards improved estimation of GFR.