Stewart B. Harris

The Prevalence of NIDDM and Associated Risk Factors in Native Canadians

OBJECTIVE To determine the true prevalence of impaired glucose tolerance (IGT), NIDDM, and associated risk factors by age and sex in an isolated native community. RESEARCH DESIGN AND METHODS A community-wide prevalence survey using a 75-g oral glucose tolerance test (OGTT) was undertaken in the remote native reserve of Sandy Lake, Ontario, Canada. Measurements for obesity included waist-to-hip circumference, BMI, and percentage body fat. RESULTS A total of 728 individuals were enrolled, representing a community participation rate of 72%. The overall crude prevalence of NIDDM was 17.2% (18.1% females and 16.0% males) and increased to 26.1% overall (28.0% females and 24.2% males) when age-standardized. The prevalence of IGT was higher in females compared with males (age-standardized prevalence of 19.8 vs. 7.1%, respectively). Females had a higher prevalence of obesity, IGT, and NIDDM occurring at younger ages. Measures of obesity and fasting insulin levels were significantly associated with NIDDM in the 18–49 age-group. CONCLUSIONS The prevalence rates of NIDDM in this study population are the highest reported to date in a Canadian native population and among the highest reported in the world. Females appear to be at much higher risk of developing obesity, IGT, and NIDDM and at a younger age. Due to the high prevalence rates of IGT and NIDDM in this young population, there is urgent need to develop culturally appropriate community-based public health intervention programs before the long-term complications of diabetes have a devastating effect on the residents.

Association of Vitamin D With Insulin Resistance and β-Cell Dysfunction in Subjects at Risk for Type 2 Diabetes

OBJECTIVE To examine cross-sectional associations of serum vitamin D [25-hydroxyvitamin D, 25(OH)D] concentration with insulin resistance (IR) and β-cell dysfunction in 712 subjects at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS Serum 25(OH)D was determined using a chemiluminescence immunoassay. Insulin sensitivity/resistance were measured using the Matsuda insulin sensitivity index for oral glucose tolerance tests (ISOGTT) and homeostasis model assessment of insulin resistance HOMA-IR. β-Cell function was determined using both the insulinogenic index (IGI) divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2). RESULTS Linear regression analyses indicated independent associations of 25(OH)D with ISOGTT and HOMA-IR (β = 0.004, P = 0.0003, and β = −0.003, P = 0.0072, respectively) and with IGI/IR and ISSI-2 (β = 0.004, P = 0.0286, and β = 0.003, P = 0.0011, respectively) after adjusting for sociodemographics, physical activity, supplement use, parathyroid hormone, and BMI. CONCLUSIONS Vitamin D may play a role in the pathogenesis of type 2 diabetes, as 25(OH)D concentration was independently associated with both insulin sensitivity and β-cell function among individuals at risk of type 2 diabetes.

Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study

BACKGROUND The evolving epidemic of type 2 diabetes has challenged health-care providers to assess the safety and efficacy of various diabetes prevention strategies. The CANOE (CAnadian Normoglycemia Outcomes Evaluation) trial investigated whether low-dose combination therapy would affect development of type 2 diabetes. METHODS In this double-blind, randomised controlled trial undertaken in clinics in Canadian centres, 207 patients with impaired glucose tolerance were randomly assigned to receive combination rosiglitazone (2 mg) and metformin (500 mg) twice daily or matching placebo for a median of 3.9 years (IQR 3.0-4.6). Randomisation was computer-generated in blocks of four, with both participants and investigators masked to treatment allocation. The primary outcome was time to development of diabetes, measured by an oral glucose tolerance test or two fasting plasma glucose values of 7.0 mmol/L or greater. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00116932. FINDINGS 103 participants were assigned to rosiglitazone and metformin, and 104 to placebo; all were analysed. Vital status was obtained in 198 (96%) participants, and medication compliance (taking at least 80% of assigned medication) was 78% (n=77) in the metformin and rosiglitazone group and 81% (n=80) in the placebo group. Incident diabetes occurred in significantly fewer individuals in the active treatment group (n=14 [14%]) than in the placebo group (n=41 [39%]; p<0.0001). The relative risk reduction was 66% (95% CI 41-80) and the absolute risk reduction was 26% (14-37), yielding a number needed to treat of 4 (2.70-7.14). 70 (80%) patients in the treatment group regressed to normal glucose tolerance compared with 52 (53%) in the placebo group (p=0.0002). Insulin sensitivity decreased by study end in the placebo group (median -1.24, IQR -2.38 to -0.08) and remained unchanged with rosiglitazone and metformin treatment (-0.39, -1.30 to 0.84; p=0.0006 between groups). The change in beta-cell function, as measured by the insulin secretion-sensitivity index-2, did not differ between groups (placebo -252.3, -382.2 to -58.0 vs rosiglitazone and metformin -221.8, -330.4 to -87.8; p=0.28). We recorded an increase in diarrhoea in participants in the active treatment group compared with the placebo group (16 [16%] vs 6 [6%]; p=0.0253). INTERPRETATION Low-dose combination therapy with rosiglitazone and metformin was highly effective in prevention of type 2 diabetes in patients with impaired glucose tolerance, with little effect on the clinically relevant adverse events of these two drugs. FUNDING GlaxoSmithKline.

Nutrition and exercise prevent excess weight gain in overweight pregnant women.

PURPOSE To determine the effect of a Nutrition and Exercise Lifestyle Intervention Program (NELIP) for overweight (OW) and obese (OB) pregnant women on pregnancy weight gain, birth weight, and maternal weight retention at 2 months postpartum. METHODS This is a single-arm intervention matched by prepregnant body mass index, age, and parity to a historical cohort (4:1). Women with a prepregnancy body mass index of > or = 25.0 kg x m(-2) (N = 65) participated in a NELIP starting at 16-20 wk of pregnancy, continuing until delivery. NELIP consisted of an individualized nutrition plan with total energy intake of approximately 2000 kcal x d(-1) (8360 kJ x d(-1)) and 40%-55% of total energy intake from carbohydrate. Exercise consisted of a walking program (30% HR reserve), three to four times per week, using a pedometer to count steps. Matched historical cohort (MC; N = 260) was from a large local perinatal database. RESULTS Weight gained by women on the NELIP was 6.8 +/- 4.1 kg (0.38 +/- 0.2 kg x wk(-1)), with a total pregnancy weight gain of 12.0 +/- 5.7 kg. Excessive weight gain occurred before NELIP began at 16 wk of gestation. Eighty percent of the women did not exceed recommended pregnancy weight gain on NELIP. Weight retention at 2 months postpartum was 2.2 +/- 5.6 kg with no difference between the OW and the OB women on NELIP. Mean birth weight was not different between NELIP (3.59 +/- 0.5 kg) and MC (3.56 +/- 0.6 kg, P > 0.05). CONCLUSIONS NELIP reduces the risk of excessive pregnancy weight gain with minimal weight retention at 2 months postpartum in OW and OB women. This intervention may assist OW and OB women in successful weight control after childbirth.

Global complication rates of type 2 diabetes in Indigenous peoples : A comprehensive review

INTRODUCTION AND OBJECTIVE The worlds Indigenous peoples are experiencing an unprecedented epidemic of type 2 diabetes [T2DM] but little has been published describing the complications burden. The objective of this paper was to conduct a systematic review of T2DM complications in Indigenous populations worldwide. METHODS A literature review was conducted using PubMed and EMBASE to examine available complications data. Country, Indigenous population, authors, publication year, total sample size, Indigenous sample size, age, methodology, and prevalence of nephropathy, end-stage renal disease, retinopathy, neuropathy, lower extremity amputations, cardiovascular disease, hospitalizations and mortality due to diabetes were recorded. RESULTS One-hundred and eleven studies were selected. Results revealed a disproportionate burden of disease complications among all Indigenous peoples regardless of their geographic location. Complication rates were seen to vary widely across Indigenous groups. DISCUSSION Gaps were found in the published literature on complications among Indigenous populations, especially those living in underdeveloped countries. These gaps may be in part due to the challenges caused by varying operational practices, research methodologies, and definitions of the term Indigenous, making documentation of rates among these peoples problematic. Comprehensive surveillance applying standardized definitions and methodologies is needed to design targeted prevention and disease management strategies for Indigenous peoples with T2DM.

HNF-1α G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community

The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A, which encodes hepatic nuclear factor-1α (HNF-1α), was associated with Oji-Cree type 2 diabetes and was found in ≈40% of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1α to activate transcription by ≈50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant negative effect of the mutant protein. The impact of the G319S mutation at the population level was assessed by classifying subjects with type 2 diabetes according to HNF1A genotype and plotting the cumulative age of onset of diabetes. Disease onset was modeled satisfactorily by two-parameter sigmoidal functions for all diabetic subjects and all three HNF1A genotypes. Pairwise statistical comparisons showed significant between-genotype differences in t50 (all P < 0.00001), corresponding to the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by ≈7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for HNF1A G319S provides a mechanistic basis for its strong association with Oji-Cree type 2 diabetes and its unparalleled specificity for diabetes prediction in these people, in whom diabetes presents a significant public health dilemma. The findings also show that HNF1A mutations can be associated with typical adult-onset insulin-resistant obesity-related diabetes in addition to maturity-onset diabetes of the young.

Prospective Associations of Vitamin D With β-Cell Function and Glycemia: The PROspective Metabolism and ISlet cell Evaluation (PROMISE) Cohort Study

OBJECTIVE To examine the prospective associations of baseline vitamin D [25-hydroxyvitamin D; 25(OH)D] with insulin resistance (IR), β-cell function, and glucose homeostasis in subjects at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS We followed 489 subjects, aged 50 ± 10 years, for 3 years. At baseline and follow-up, 75-g oral glucose tolerance tests (OGTTs) were administered. IR was measured using the Matsuda index (ISOGTT) and the homeostasis model assessment of IR (HOMA-IR), β-cell function was determined using both the insulinogenic index divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2), and glycemia was assessed using the area under the glucose curve (AUCglucose). Regression models were adjusted for age, sex, ethnicity, season, and baseline value of the outcome variable, as well as baseline and change in physical activity, vitamin D supplement use, and BMI. RESULTS Multivariate linear regression analyses indicated no significant association of baseline 25(OH)D with follow-up ISOGTT or HOMA-IR. There were, however, significant positive associations of baseline 25(OH)D with follow-up IGI/IR (β = 0.005, P = 0.015) and ISSI-2 (β = 0.002, P = 0.023) and a significant inverse association of baseline 25(OH)D with follow-up AUCglucose (β = −0.001, P = 0.007). Progression to dysglycemia (impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes) occurred in 116 subjects. Logistic regression analyses indicated a significant reduced risk of progression with higher baseline 25(OH)D (adjusted odds ratio 0.69 [95% CI 0.53–0.89]), but this association was not significant after additional adjustment for baseline and change in BMI (0.78 [0.59–1.02]). CONCLUSIONS Higher baseline 25(OH)D independently predicted better β-cell function and lower AUCglucose at follow-up, supporting a potential role for vitamin D in type 2 diabetes etiology.

Pedometer-determined ambulatory activity in individuals with type 2 diabetes

This cross-sectional study presents the first normative data on pedometer-determined ambulatory activity, defined as steps/day, in 160 (98 males, 62 females; age=52.4 +/- 5.3 years; BMI=32.3 +/- 5.7) free-living individuals with type 2 diabetes. Participants took 6662 +/- 3077 steps per day, less than that reported in nondiabetic samples and more than that reported for samples living with more restrictive chronic conditions including claudication, joint replacement, chronic obstructive lung disease, and chronic heart failure. Steps/day and BMI were inversely and significantly correlated (r=-0.27, P<0.01). Further, there was a significant difference between BMI categories (from normal weight to obesity class III) with regard to steps/day (F=2.96, P<0.05). The difference was most apparent between the highest obesity classes (II and III) and normal weight categories. This data is useful for sample comparison purposes. In addition the standard deviation or variance estimates can be used to calculate samples sizes for intervention efforts. Objective quantification of ambulatory activity via simple and inexpensive pedometers permits researchers and practitioners to easily screen for level of activity along a continuum. This study opens the door for future research and clinical applications including identifying threshold values related to important health outcomes and evaluating incremental change due to various interventions in this population.

Preliminary outcome evaluation of the First Step Program: a daily physical activity intervention for individuals with type 2 diabetes

The First Step Program uses simple and inexpensive pedometers to incrementally increase walking behaviors in sedentary individuals with type 2 diabetes. The pilot sample consisted of nine individuals (six women, three men; group mean age 53+/-6; group mean body mass index=32.9+/-3.4kg/m(2)). A timed self-paced walk while wearing the pedometer allowed for the conversion of changes in pedometer steps per day to time in minutes per day. There was an immediate and dramatic increase in walking behavior (an average of 34.3min of walking a day) that was sustained even 2 months post-intervention and after withdrawal of contact (an average of 22.6min of walking a day). Improvements in other outcomes (systolic blood pressure and waist girth) support a valid change in behavior. Although preliminary, these results warrant further investigation of such approaches.

Association of 25(OH)D and PTH with Metabolic Syndrome and Its Traditional and Nontraditional Components

CONTEXT Emerging evidence suggests that 25-hydroxy vitamin D [25(OH)D] and PTH may play a role in the etiology of the metabolic syndrome (MetS). However, evidence to date is limited and inconsistent, and few studies have examined associations with nontraditional MetS components. OBJECTIVE The objective of the study was to examine the association of vitamin D and PTH with MetS and its traditional and nontraditional components in a large multiethnic sample. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, we examined 654 participants from London and Toronto, Ontario, Canada, aged 30 yr and older with risk factors for type 2 diabetes. MAIN OUTCOME MEASURES Presence of MetS and its traditional and nontraditional components was measured. RESULTS Approximately 43% of the study participants were classified as having MetS. Higher 25(OH)D was significantly associated with a reduced presence of MetS after adjustment for age, sex, season, ethnicity, supplement use, physical activity, and PTH (odds ratio 0.76, 95% confidence interval 0.62-0.93). PTH was not associated with the presence of MetS after multivariate adjustment. Multivariate linear regression analyses indicated significant adjusted inverse associations of 25(OH)D with waist circumference, triglyceride level, fasting insulin, and alanine transaminase (P < 0.041). Elevated PTH was positively associated with waist circumference and high-density lipoprotein cholesterol (P < 0.04). Other associations between PTH and MetS components were attenuated after adjustment for adiposity. CONCLUSIONS Serum 25(OH)D, but not PTH, was significantly associated with MetS as well as a number of MetS components after multivariate adjustment. These results suggest that low 25(OH)D may play a role in the etiology of the MetS.