Association of type 2 diabetes susceptibility loci with one-year weight loss in the look AHEAD clinical trial

The importance of lifestyle intervention for the prevention and treatment of type 2 diabetes (T2D) has been underscored by the limited benefit of pharmacologic therapies. We sought to determine whether genetic variants that contribute to T2D risk modify the response of weight and waist circumference to an intensive lifestyle intervention (ILI) in patients with obesity and T2D. Look AHEAD (Action for Health in Diabetes) is a randomized clinical trial comparing an ILI with a control condition on the risk of cardiovascular disease in overweight adults with T2D. We analyzed 28 single-nucleotide polymorphisms (SNPs) at/near 17 T2D-susceptibility genes in 3,903 consented participants. We genetically characterized the cohort by assessing whether T2D-susceptibility loci were overrepresented compared with a nondiabetic community-based cohort (N = 1,016). We evaluated the association of individual variants and a composite genetic risk score (GRS) with anthropometric traits at baseline and after 1-year of intervention. Look AHEAD subjects carried more T2D-susceptibility alleles than the control population. At baseline, TCF7L2 risk alleles and the highest GRS were associated with lower BMI and waist circumference. Nominally significant genotype-by-intervention interactions were detected for 1-year change in waist circumference with JAZF1, MTNR1B, and IRS1, and BMI with JAZF1. Highest GRS was associated with a greater reduction in waist circumference at year 1, although the variance in change attributable to the GRS was small. This study shows that the genetic burden associated with T2D risk does not undermine the effect of lifestyle intervention and suggests the existence of additional genomic regions, distinct from the T2D-susceptibility loci, which may enhance or mitigate weight loss.     

Randomized controlled trial of chewing gum for weight loss

The possible effects on body weight of chewing gum on a regular schedule have not been tested in a randomized controlled trial (RCT). We conducted an 8-week RCT in 201 overweight and obese adults to test the hypothesis that receiving printed material on good nutrition and chewing gum for a minimum of 90 min/day (n = 102) would lead to greater weight loss than receiving printed nutrition information only (n = 99). Changes in BMI, waist circumference, and blood pressure were secondary outcomes. Adherence to the gum-chewing protocol in the intervention group was >95%. In the intention-to-treat analysis, there were virtually no changes in weight or BMI in either group between baseline and the end of the intervention at 8 weeks. Waist circumference decreased significantly in the intervention group between baseline and 8 weeks (mean ± SD change = -1.4 ± 5.3 cm; P = 0.0128); however, there was no significant difference in change in waist circumference comparing the groups. Similarly, systolic and diastolic blood pressure decreased significantly in the intervention group between baseline and 8 weeks (-3.0 ± 9.9 mm Hg; P = 0.0032 and -3.2 ± 7.3 mm Hg; P = 0.0001, respectively); however, there were no significant differences in the changes in systolic or diastolic blood pressure between the groups. Analyses including completers only produced essentially the same results. We conclude that chewing gum on a regular schedule for 8 weeks did not facilitate weight loss in these overweight and obese adults.     

Randomized trial of a multifaceted commercial weight loss program

Objective: To test whether a commercial weight loss program promotes greater weight loss in overweight or obese women compared with control conditions and to describe the effect on plasma lipids, carotenoids, hormones, and fitness. Research Methods and Procedures: Overweight or obese women were randomized to commercial weight loss program or control conditions (n = 35 each). Results: At randomization, participants were 41.1 (11.4) (mean [standard deviation]) years, BMI 34.0 (3.5) kg/m², and weight 92.0 (11.1) kg. At 6 months, change in weight by intent‐to‐treat (ITT) analysis was ?7.2 (6.7) kg and ?7.8% (7.2%) in the intervention group vs. ?0.3 (3.9) kg and ?0.3% (4.5%) in the control group (n = 35 for each; p < 0.01). One‐year ITT analysis revealed significantly greater change in weight, percent weight, BMI, and waist and hip circumferences in the intervention vs. control group. Completers at 1 year exhibited change in weight of ?7.3 (10.4) kg for the intervention group (n = 32) vs. ?0.7 (5.6) kg for controls (n = 33) (p < 0.01), and ?7.8% (11.1%) weight change for the intervention group vs. ?0.7% (6.2%) for controls (p < 0.01). High‐density lipoprotein (HDL) cholesterol concentration increased significantly in the intervention group. Fasting serum insulin decreased in the intervention but increased in the control group at 6 months (p < 0.01), remaining different at 1 year (p = 0.05). Discussion: The commercial program successfully facilitated weight loss, which was notably maintained at 1 year, and promoted favorable changes in plasma lipid and hormone concentrations.     

Randomised controlled trial of structured personal care of type 2 diabetes mellitus

ObjectiveTo assess the effect of a multifaceted intervention directed at general practitioners on six year mortality, morbidity, and risk factors of patients with newly diagnosed type 2 diabetes.DesignPragmatic, open, controlled trial with randomisation of practices to structured personal care or routine care; analysis after 6 years.Setting311 Danish practices with 474 general practitioners (243 in intervention group and 231 in comparison group).Participants874 (90.1%) of 970 patients aged ⩾40 years who had diabetes diagnosed in 1989-91 and survived until six year follow up.InterventionRegular follow up and individualised goal setting supported by prompting of doctors, clinical guidelines, feedback, and continuing medical education.ResultsPredefined non-fatal outcomes and mortality were the same in both groups. The following risk factor levels were lower for intervention patients than for comparison patients (median values): fasting plasma glucose concentration (7.9 v 8.7 mmol/l, P=0.0007), glycated haemoglobin (8.5% v 9.0%, P<0.0001; reference range 5.4-7.4%), systolic blood pressure (145 v 150 mm Hg, P=0.0004), and cholesterol concentration (6.0 v 6.1 mmol/l, P=0.029, adjusted for baseline concentration). Both groups had lost weight since diagnosis (2.6 v 2.0 kg). Metformin was the only drug used more frequently in the intervention group (24% (110/459) v 15% (61/415)).Intervention doctors arranged more follow up consultations, referred fewer patients to diabetes clinics, and set more optimistic goals.ConclusionsIn primary care, individualised goals with educational and surveillance support may for at least six years bring risk factors of patients with type 2 diabetes to a level that has been shown to reduce diabetic complications but without weight gain.

What is already known on this topic

Evidence is increasing that control of hyperglycaemia, hypertension, and dyslipidaemia may postpone the development of diabetic complications in patients with type 2 diabetesMaintaining good control over a long period can be difficult

What this study adds

Structured individualised personal care with educational and surveillance support for general practitioners reduced levels of risk factors in type 2 diabetic patients after six yearsRisk factors were reduced to a level that has been shown to have a beneficial effect on diabetic complicationsParticipants also showed modest weight loss     

Metabolic surgery for type 2 diabetes mellitus

Background: Metabolic surgery for morbid obesity induces significant weight loss and resolution of many obesity-related comorbidities, the most notable of which is remission of type 2 diabetes mellitus (DM). Such changes seem to precede significant weight loss in this population shortly after undergoing diversionary procedures.Objective: This article explores the evidence for salutary metabolic benefits of bariatric surgery, with special emphasis on glycemic control and remission of type 2 DM.Methods: We conducted a query of the PubMed database for articles published in English within the past 15 years using the search terms bariatric surgery, obesity, type 2 diabetes, gastric bypass, gastric banding, incretins, enteroinsular axis, GLP-1 (glucagon-like peptide-1), and GIP (glucose-dependent insulinotropic polypeptide). We targeted review articles as well as those discussing the effects of bariatric surgery on the enteroinsular axis and the respective effects on glyce-mic control.Results: Most of the clinical reports indicated a high remission rate (≥85%) for type 2 DM, and relatively higher rates in patients who underwent diversionary procedures. Studies with small cohorts and laboratory data suggested a role for gastrointestinal hormones in the regulation of glucose homeostasis after bariatric surgery.Conclusions: Gastrointestinal surgery for severe obesity, through restrictive and/or neurohormonal effects, is an effective treatment for type 2 DM. Surgically induced weight loss was found to be sustainable, durable, and associated with remission of type 2 DM, a reduction in mortality, and improvement in quality of life.     

Pregnancy loss and neonatal death in women with type 1 or type 2 diabetes mellitus

Background: Diabetes mellitus (DM) is known to be a significant risk factor for pregnancy loss, either through still-birth or late intrauterine death or as the result of severe congenital malformation. Improved glycemic control and other advances in care substantially reduced the incidence of pregnancy loss in women with type 1 DM in most countries by the 1970s. However, because of a greater prevalence of obesity since the 1980s, the emergence of type 2 DM in pregnancy has become a significant problem. Although more pregnancies now occur in women with type 2 DM than in those with type 1 DM in many locations, relatively little information has been published about pregnancy loss in type 2 DM.Objectives: This article examines the prevalence and causes of pregnancy loss in type 1 and type 2 DM and identifies factors in addition to glycemic control that may influence pregnancy outcome.Methods: A MEDLINE search was conducted for recent literature on pregnancy loss in DM. Series reporting >200 pregnancies in type 1 DM and/or >100 pregnancies in type 2 DM were included.Results: Thirty-four studies were identified (15 in type 1 DM [1997-2007], 19 in type 2 DM [1986-2007]). In type 1 DM, major congenital anomalies now account for ~50% of pregnancy losses, and all-cause perinatal mortality remains higher than in the general population. Several studies have suggested that the perinatal mortality rate is higher in type 2 DM than in type 1 DM. Factors other than glycemic control probably explain this phenomenon: women with type 2 DM typically are older and more obese, and they come from disadvantaged communities—all risk factors for pregnancy loss, particularly late intrauterine death and chorioamnionitis. In some women, type 2 DM may be recognized for the first time during pregnancy; pregnancies in these women carry the same risks of pregnancy loss as those in women with established DM.Conclusions: Demographic changes in the prevalence of obesity suggest that the prevalence of type 2 DM in pregnancy will almost certainly increase. Although meticulous glycemic control is undoubtedly important in achieving good pregnancy outcomes, clinicians should be aware of the multiple risk factors faced by women with DM.     

Metabolic effects of fluoxetine in adults with type 2 diabetes mellitus: a meta-analysis of randomized placebo-controlled trials

Background

The prevalence of obesity and diabetes is increasing dramatically throughout the world. Studies have shown that excess adiposity is a critical predictor of new onset T2DM. This meta-analysis is aimed to assess the metabolic effects of fluoxetine in T2DM.

Methods and Findings

Electronic search was conducted in the database Medline, PubMed, EMBASE, and the Cochrane library, from inception through to March 2011. A systematic review of the studies on the metabolic effects of fluoxetine in T2DM was performed. The weighted mean difference (WMD) and its 95% CI were calculated from the raw data extracted from the original literature. The software Review Manager (version 4.3.1) and Stata (version 11.0) were applied for meta-analysis. Five randomized, placebo-controlled trials were included in the meta-analysis. According to WMD calculation, fluoxetine therapy led to 4.27 Kg of weight loss (95%CI 2.58–5.97, P<0.000 01), 1.41 mmol/L of fasting plasma glucose (FPG) decrement (95%CI 0.19–2.64, P = 0.02) and 0.54 mmol/L of triglyceride (TG) reduction (95%CI 0.35–0.73, P<0.000 01) compared with placebo. Moreover, fluoxetine therapy produced 0.78% of HbA1c decrement (95%CI −0.23–1.78). However, this effect was not statistically significant (P = 0.13).

Conclusions

Short period of fluoxetine therapy can lead to weight loss as well as reduction of FPG, HbA1c and TG in T2DM.     

Randomized controlled trial testing weight loss and abdominal obesity outcomes of moxibustion

Background

The purpose of this study was to investigate the efficacy of moxibustion therapy on weight loss, waist circumference and waist-to-hip ratio in young adult females. An experimental design, 51 Asian females were enrolled. Inclusion criteria included females with ages between 21 and 25 years-old and waist circumference?≥?80 cm, and the exclusion criteria included intolerance to moxibustion therapy and current illness. Two groups were formed, and the subjects in the experimental group received moxibustion sessions lasting 20 min and an educational video program for 30 min; however, participants in the control group received only the educational program every other week for 8 weeks. Dependent variable measurements (e.g., body weight, waist circumference and waist-to-hip ratio) were collected at baseline and follow-up for 8 weeks.

Results

Average body weight of the treatment group decreased significantly from ??1.478 kg (p?<?0.0001), while the average body weight in the control group did not decrease significantly ??0.038 kg (p?=?0.7197). Also, individuals in the moxibustion experimental group showed significant reductions (p?<?0.0001) in both waist circumference and waist-to-hip ratio.

Conclusion

Positive effects on anthropometry can be achieved by moxibustion intervention in conjunction with a weight loss education program. Especially waist circumference and waist-to-hip ratio had more clinically significant and more pronounced for health reasons Future studies can focus on the functional assessment of biomarkers associated with the immune system and relevant mechanisms of action.

     

Oral antihyperglycemic therapy for type 2 diabetes mellitus

DIABETES MELLITUS IS A CHRONIC DISEASE that is growing in prevalence worldwide. Pharmacologic therapy is often necessary to achieve optimal glycemic control in the management of diabetes. Orally administered antihyperglycemic agents (OHAs) can be used either alone or in combination with other OHAs or insulin. The number of available OHAs has increased significantly in the last decade, which translates into more therapeutic options and complex decision-making for physicians. This review article is designed to help with these decisions. We review the mechanism of action, efficacy and side effects of the different classes of OHAs (α-glucosidase inhibitors, biguanides, insulin secretagogues, insulin sensitizers and intestinal lipase inhibitor) and discuss the current recommendations for their use.Diabetes mellitus is a chronic disease that is growing in prevalence worldwide.¹ Canadian data from the National Diabetes Surveillance Strategy demonstrate a prevalence of 4.8% among adults, with the vast majority having type 2 diabetes.²With the growing elderly Canadian population, the rising prevalence of obesity and the alarming increase in childhood and adolescent type 2 diabetes, the burden of this disease will continue to grow. Aggressive glycemic control has been demonstrated to decrease microvascular^3,4,5 and perhaps macrovascular^6,7 complications, although the latter claim remains controversial. The Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada⁸ recommends a target hemoglobin A_1c concentration of 7.0% or less for all patients with diabetes and, for those in whom it can be safely achieved, a target hemoglobin A_1c concentration in the normal range (usually ≤ 6.0%).⁸ Although nonpharmacologic therapy (e.g., diet, exercise and weight loss) remains a critical component in the treatment of diabetes, pharmacologic therapy is often necessary to achieve optimal glycemic control. Orally administered antihyperglycemic agents (OHAs) can be used either alone or in combination with other OHAs or insulin. The number of available OHAs has increased significantly in the last decade, which translates into more therapeutic options and complex decision-making. This article reviews the mechanism of action, efficacy and side effects of each OHA drug class (α-glucosidase inhibitors, biguanides, insulin secretagogues, insulin sensitizers and intestinal lipase inhibitor) and the current recommendations for their use.     

A randomized,placebo-controlled clinical trial evaluating the safety and efficacy of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus inadequately controlled by glimepiride and metformin

Background

Type 2 diabetes (T2D) is a progressive disease that often requires a patient to use multiple antihyperglycemic agents to achieve glycemic control with disease progression. Omarigliptin is a once-weekly dipeptidyl peptidase-4 inhibitor. The purpose of this trial was to assess the efficacy and safety of adding omarigliptin to the treatment regimen of patients with T2D inadequately controlled by dual therapy with metformin and glimepiride.

Methods

Patients with T2D and HbA1c ≥7.5% and ≤10.5% while on metformin (≥1500 mg/day) and glimepiride (≥4 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 154) or placebo (N = 153) for 24 weeks. The primary objective was to assess whether omarigliptin was superior to placebo in reducing HbA1c at Week 24. Secondary objectives were to assess the effects of omarigliptin vs. placebo on FPG and the proportion of subjects attaining HbA1c goals of <7% and <6.5%.

Results

From a mean baseline HbA1c of 8.5% (omarigliptin) and 8.6% (placebo), the least squares (LS) mean change from baseline in HbA1c at Week 24 was ?0.67% in the omarigliptin group and ?0.06% in the placebo group, with a between-group difference (95% CI) of ?0.61% (?0.85, ?0.38). Treatment with omarigliptin resulted in a significantly greater reduction in FPG relative to placebo (LS mean difference [95% CI] -0.9 mmol/L [?1.4, ?0.4]; p < 0.001). The proportion of patients achieving glycemic goals of <7.0% and <6.5% was higher in the omarigliptin group relative to the placebo group. The overall incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuations were generally similar between treatment groups. The incidence of symptomatic hypoglycemia was 10.5% in the omarigliptin group and 8.5% in the placebo group. Relative to baseline, omarigliptin and placebo treatments were associated with LS mean changes in body weight of ?0.1 kg and ?0.9 kg, respectively.

Conclusion

In patients with T2D and inadequate glycemic control on dual therapy with metformin and glimepiride, compared with placebo, once-weekly omarigliptin provided greater improvement in glycemic control and was generally well tolerated.

Trial registration

ClinicalTrials.gov: NCT01704261, EudraCT Number: 2012-002612-10. Trial Registration Date: October 8, 2012.

     

Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial.

Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with alpha-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different alpha-lipoic acid groups, all subjects receiving ALA were combined in the "active" group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations.     

Chromium determinations in blood cells: clinical relevance demonstrated in patients with diabetes mellitus type 2

As an essential nutrient involved in carbohydrate and lipid metabolism, chromium is of extraordinary importance for patients with diabetes. Plasma concentrations do not reflect the chromium supply; thus, we determined the element’s content in blood cells in order to evaluate the body status. We investigated 86 blood donors (C) and 35 diabetics type 2 (Dm2). After the isolation of the blood cells by using a density centrifugation, the chromium concentrations were determined by electrothermal atomic absorption spectrometry. Compared to C, Dm2 had higher values in plasma, erythrocytes, and platelets (248%, 61%, and 91%, respectively) and lower contents in polymorphonuclear and mononuclear leukocytes (each −35%, age- and sex-matched groups with n=35, each p<0.01). The poorer the metabolic control assessed by HbA1c, the higher were the chromium concentrations in plasma (r=+0.46, n=33, p=0.007, increase 11.1% per %HbA1c) and the lower were the values in mononuclear leukocytes (r=−0.45, n=33, p=0.008, decrease 17.8% per %HbA1c). The changed amounts in plasma and in mononuclear cells in increasing hyperglycemia could be the result of an intracellular/extracellular redistribution of the element. High plasma levels might explain the renal chromium losses of diabetics, whereas the lymphocytes could reflect a decreasing chromium body state.     

Development and characterization of a novel rat model of type 2 diabetes mellitus: the UC Davis type 2 diabetes mellitus UCD-T2DM rat

The prevalence of type 2 diabetes (T2DM) is increasing, creating a need for T2DM animal models for the study of disease pathogenesis, prevention, and treatment. The purpose of this project was to develop a rat model of T2DM that more closely models the pathophysiology of T2DM in humans. The model was created by crossing obese Sprague-Dawley rats with insulin resistance resulting from polygenic adult-onset obesity with Zucker diabetic fatty-lean rats that have a defect in pancreatic beta-cell function but normal leptin signaling. We have characterized the model with respect to diabetes incidence; age of onset; longitudinal measurements of glucose, insulin, and lipids; and glucose tolerance. Longitudinal fasting glucose and insulin data demonstrated progressive hyperglycemia (with fasting and fed glucose concentrations >250 and >450 mg/dl, respectively) after onset along with hyperinsulinemia resulting from insulin resistance at onset followed by a progressive decline in circulating insulin concentrations, indicative of beta-cell decompensation. The incidence of diabetes in male and female rats was 92 and 43%, respectively, with an average age of onset of 6 mo in males and 9.5 mo in females. Results from intravenous glucose tolerance tests, pancreas immunohistochemistry, and islet insulin content further support a role for beta-cell dysfunction in the pathophysiology of T2DM in this model. Diabetic animals also exhibit glycosuria, polyuria, and hyperphagia. Thus diabetes in the UC Davis-T2DM rat is more similar to clinical T2DM in humans than in other existing rat models and provides a useful model for future studies of the pathophysiology, treatment, and prevention of T2DM.