Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

OBJECTIVE: Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. RESEARCH DESIGN AND METHODS: We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. RESULTS: We replicated the association of variants in the metformin transporter gene $SLC47A1$ with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene $STK11$, the AMPK subunit genes $PRKAA1$ and $PRKAA2$, and a missense SNP in $SLC22A1$, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene $PRKAG2$ (hazard ratio 1.24, 95% CI 1.09–1.40, P = 7 × 10$^{−4}$). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest $P$ values were consistent with experiment-wide 33% false discovery rates. CONCLUSIONS: We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples

Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

OBJECTIVE: Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. RESEARCH DESIGN AND METHODS: We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. RESULTS: We replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09-1.40, P = 7 × 10(-4)). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates. CONCLUSIONS: We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.

BACKGROUND: Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors--elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle--are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. METHODS: We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. RESULTS: The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. CONCLUSIONS: Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin

The community-based prevention of diabetes (ComPoD) study: A randomised, waiting list controlled trial of a voluntary sector-led diabetes prevention programme

© 2019 The Author(s). Objective: This two-site randomised trial compared the effectiveness of a voluntary sector-led, community-based diabetes prevention programme to a waiting-list control group at 6 months, and included an observational follow-up of the intervention arm to 12 months. Methods: Adults aged 18-75 years at increased risk of developing type 2 diabetes due to elevated blood glucose and being overweight were recruited from primary care practices at two UK sites, with data collected in participants' homes or community venues. Participants were randomised using an online central allocation service. The intervention, comprising the prototype "Living Well, Taking Control" (LWTC) programme, involved four weekly two-hour group sessions held in local community venues to promote changes in diet and physical activity, plus planned follow-up contacts at two, three, six, nine and 12 months alongside 5 hours of additional activities/classes. Waiting list controls received usual care for 6 months before accessing the programme. The primary outcome was weight loss at 6 months. Secondary outcomes included glycated haemoglobin (HbA1c), blood pressure, physical activity, diet, health status and well-being. Only researchers conducting analyses were blinded. Results: The target sample of 314 participants (157 each arm) was largely representative of local populations, including 44% men, 26% from ethnic minorities and 33% living in deprived areas. Primary outcome data were available for 285 (91%) participants (141 intervention, 144 control). Between baseline and 6 months, intervention participants on average lost more weight than controls (- 1.7 kg, 95% CI - 2.59 to - 0.85). Higher attendance was associated with greater weight loss (- 3.0 kg, 95% CI - 4.5 to - 1.5). The prototype LWTC programme more than doubled the proportion of participants losing > 5% of their body weight (21% intervention vs. 8% control, OR 2.83, 95% CI 1.36 to 5.90) and improved self-reported dietary behaviour and health status. There were no impacts on HbA1c, blood pressure, physical activity and well-being at 6 months and, amongst intervention participants, few further changes from six to 12-months (e.g. average weight re-gain 0.36 kg, 95% CI - 0.20 to 0.91). There were no serious adverse events but four exercise-related injuries were reported in the intervention arm. Conclusions: This voluntary sector-led diabetes prevention programme reached a broad spectrum of the population and had modest effects on weight-related outcomes, but limited impacts on other diabetes risk factors. Trial registration: Trial registration number: ISRCTN70221670, 5 September 2014 Funder (National Institute for Health Research School for Public Health Research) project reference number: SPHR-EXE-PES-COM

Feline orofacial pain syndrome (FOPS): a retrospective study of 113 cases

Feline orofacial pain syndrome (FOPS) is a pain disorder of cats with behavioural signs of oral discomfort and tongue mutilation. This report describes the findings from a case series of 113 cats including 100 Burmese. FOPS is suspected to be a neuropathic pain disorder and the predominance within the Burmese cat breed suggests an inherited disorder, possibly involving central and/or ganglion processing of sensory trigeminal information. The disease is characterised by an episodic, typically unilateral, discomfort with pain-free intervals. The discomfort is triggered, in many cases, by mouth movements. The disease is often recurrent and with time may become unremitting - 12% of cases in this series were euthanased as a consequence of the condition. Sensitisation of trigeminal nerve endings as a consequence of oral disease or tooth eruption appears to be an important factor in the aetiology - 63% of cases had a history of oral lesions and at least 16% experienced their first sign of discomfort during eruption of permanent teeth. External factors can also influence the disease as FOPS events could be directly linked to a situation causing anxiety in 20% of cats. FOPS can be resistant to traditional analgesics and in some cases successful management required anti-convulsants with an analgesic effect

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

Background Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors — elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle — are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. Methods We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. Results The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Conclusions Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin

Confirming glycemic status in the diabetes prevention program: Implications for diagnosing diabetes in high risk adults

AIMS: To examine the ability of FPG and/or 2-hr glucose to confirm diabetes and to determine the proportion of participants with HbA1c ≥6.5%. METHODS: Diabetes confirmation rates were calculated after a single elevated FPG and/or 2-hr glucose on an oral glucose tolerance test (OGTT) using a confirmatory OGTT performed within 6 weeks. RESULTS: 772 (24%) participants had elevated FPG or 2-hr glucose on an OGTT that triggered a confirmation visit. There were 101 triggers on FPG alone, 574 on 2-hr glucose alone, and 97 on both. Only 47% of participants who triggered had confirmed diabetes. While the confirmation rate for FPG was higher than that for 2-hr glucose, the larger number of 2-hr glucose triggers resulted in 87% of confirmed cases triggering on 2-hr glucose. Confirmation rates increased to 75% among persons with FPG ≥126 mg/dl and HbA1c ≥6.5%. CONCLUSIONS: Only half of persons with elevated FPG and IGT were subsequently confirmed to have diabetes. At current diagnostic levels, more persons trigger on 2-hr glucose than on FPG, but fewer of these persons have their diagnoses confirmed. In individuals with FPG ≥126 mg/dl and HbA1c ≥6.5%, the confirmation rate was increased

Lifestyle Intervention Improves Heart Rate Recovery from Exercise in Adults with Type 2 Diabetes: Results from the Look AHEAD Study

The primary aims of this paper were (1) to evaluate the influence of intensive lifestyle weight loss and exercise intervention (ILI) compared with diabetes support and education (DSE) upon Heart Rate Recovery (HRR) from graded exercise testing (GXT) and (2) to determine the independent and combined effects of weight loss and fitness changes upon HRR. In 4503 participants (45–76 years) who completed 1 year of intervention, HRR was measured after a submaximal GXT to compare the influence of (ILI) with (DSE) upon HRR. Participants assigned to ILI lost an average 8.6% of their initial weight versus 0.7% in DSE group (P<0.001) while mean fitness increased in ILI by 20.9% versus 5.8% in DSE (P<0.001). At Year 1, all exercise and HRR variables in ILI improved (P<0.0001) versus DSE: heart rate (HR) at rest was lower (72.8±11.4 versus 77.7±11.7 b/min), HR range was greater (57.7±12.1 versus 53.1±12.4 b/min), HR at 2 minutes was lower (89.3±21.8 versus 93.0±12.1 b/min), and HRR was greater (41.25±22.0 versus 37.8±12.5 b/min). Weight loss and fitness gain produced significant separate and independent improvements in HRR