Safety and efficacy of insulin degludec/liraglutide (IDegLira) added to sulphonylurea alone or to sulphonylurea and metformin in insulin-naïve people with Type 2 diabetes: the DUAL IV trial.

AIM: To investigate the safety and efficacy of insulin degludec/liraglutide (IDegLira), a novel combination product, as add-on therapy for people with Type 2 diabetes uncontrolled on sulphonylurea therapy. METHODS: In this 26-week, double-blind trial, adults with Type 2 diabetes [HbA1c 53-75 mmol/mol (7.0-9.0%)] were randomized to IDegLira (n = 289) or placebo (n = 146) as add-on to pre-trial sulphonylurea ± metformin, titrating to a fasting glycaemic target of 4.0-6.0 mmol/l. Treatment initiation was at 10 dose steps, and maximum dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). RESULTS: The mean HbA1c decreased from 63 mmol/mol (7.9%) to 46 mmol/mol (6.4%) with IDegLira and to 57 mmol/mol (7.4%) with placebo [estimated treatment difference -11 mmol/mol (95% CI -13; -10) or -1.02% (95% CI -1.18; -0.87); P < 0.001]. The HbA1c target of 53 mmol/mol (<7%) was achieved by 79.2% of participants in the IDegLira group vs 28.8% in the placebo group [estimated odds ratio 11.95 (95% CI 7.22; 19.77); P < 0.001]. Mean weight change was +0.5 kg with IDegLira vs -1.0 kg with placebo [estimated treatment difference 1.48 kg (95% CI 0.90; 2.06); P < 0.001]. Confirmed hypoglycaemia occurred in 41.7 and 17.1% of IDegLira- and placebo-treated participants, respectively, with rates of 3.5 vs 1.4 events/patient-years of exposure [estimated rate ratio 3.74 (95% CI 2.28; 6.13); P < 0.001]. IDegLira was generally well tolerated. The rates of serious adverse events were 20.3 and 8.0 per 100 patient-years of exposure with IDegLira and placebo, respectively, without obvious patterns in the type of events. CONCLUSIONS: IDegLira can be used in people uncontrolled with sulphonylurea ± metformin to improve efficacy with a safety profile in line with previous DUAL trials.

A comparison of the assessment and management of cardiometabolic risk in patients with and without type 2 diabetes mellitus in Canadian primary care.

AIM: To investigate the cardiometabolic risk (CMR) assessment and management patterns for individuals with and without type 2 diabetes mellitus (T2DM) in Canadian primary care practices. METHODS: Between April 2011 and March 2012, physicians from 9 primary care teams and 88 traditional non-team practices completed a practice assessment on the management of 2461 patients >40 years old with no clinical evidence of cardiovascular disease and diagnosed with at least one of the following risk factor-T2DM, dyslipidaemia or hypertension. RESULTS: There were 1304 individuals with T2DM and 1157 without. Pharmacotherapy to manage hyperglycaemia, dyslipidaemia and hypertension was widely prescribed. Fifty-eight percent of individuals with T2DM had a glycated haemoglobin (HbA1c) ≤7.0%. Amongst individuals with dyslipidaemia, median low-density lipoprotein cholesterol (LDL-C) was 1.8 mmol/l for those with T2DM and 2.8 mmol/l for those without. Amongst individuals with hypertension, 30% of those with T2DM achieved the <130/80 mmHg target, whereas 60% of those without met the <140/90 mmHg target. The composite glycaemic, LDL-C and blood pressure (BP) target outcome was achieved by 12% of individuals with T2DM. Only 17% of individuals with T2DM and 11% without were advised to increase their physical activity. Dietary modifications were recommended to 32 and 10% of those with and without T2DM, respectively. CONCLUSIONS: Patients at elevated CMR were suboptimally managed in the primary care practices surveyed. There was low attainment of recommended therapeutic glycaemic, lipid and BP targets. Advice on healthy lifestyle changes was infrequently dispensed, representing a missed opportunity to educate patients on the long-term benefits of lifestyle modification.

Harmonization of criteria and terminology in fetal rat skeletal evaluations.

BACKGROUND: A survey of laboratories in North American and Europe that routinely conduct fetal skeletal examinations was performed with the purpose of (1) understanding current terminology used for classifying skeletal findings in developmental toxicity (DT) studies and (2) understanding the criteria used to identify relatively common findings that sufficiently deviate from normal. The goal was to promote terminology harmonization and improve interlaboratory consistency in the criteria used to identify developmental anomalies. METHODS: The survey, designed based on terminology for developmental anomalies recommended by an international collaboration (Makris et al., Congenital Anomalies, 2009;49(3):123-246), was conducted by a subgroup (authors of this publication) of the Royal Society of Biology's International Register of Fetal Morphologists (IRFM). RESULTS: Individual and summarized anonymized responses are provided here. The authors, who are expert fetal morphologists with experience performing fetal examinations, reviewed the responses and generated recommendations on preferred terminology and criteria for determining when morphological variations deviate from normal and warrant recording of the findings for skeletal observations in Sprague Dawley (SD) fetal rats. The objective of these recommendations is to complement Makris et al. (Congenital Anomalies, 2009;49(3):123-246). CONCLUSION: The broad application will improve interlaboratory harmonization of recording fetal skeleton findings in developmental toxicity studies intended for regulatory submissions, including SEND (Standard for Exchange of Nonclinical Data).

Increased rates of adverse outcomes for gestational diabetes and pre-pregnancy diabetes in on-reserve First Nations Women in Ontario, Canada.

AIMS: To compare the prevalence of diabetes in pregnancy, pregnancy care and adverse pregnancy outcomes in on-reserve First Nations women vs. non-First Nations women in Ontario, Canada. METHODS: A retrospective population-based cohort study was performed. All 487368 live singleton hospital deliveries between 1 April 2002 and 31 March 2010 were identified. Outcomes were defined by linking mothers and infants to provincial healthcare administrative databases. RESULTS: Diabetes in pregnancy was more prevalent in First Nations women (10.3 vs. 6.0%). They received less pregnancy care and had higher rates of adverse outcomes than non-First Nations women with diabetes. CONCLUSIONS: First Nations women are at a higher risk of diabetes in pregnancy and adverse outcomes. This highlights the need for increased care for pregnant First Nations women.

Discordant effects on central obesity, hepatic insulin resistance, and alanine aminotransferase of low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance.

Alanine aminotransferase (ALT) predicts incident type 2 diabetes (T2DM), possibly reflecting early fatty liver and hepatic insulin resistance. Thiazolidinediones and metformin can improve fatty liver and hepatic insulin resistance, respectively. In the Canadian Normoglycemia Outcome Evaluation trial, rosiglitazone/metformin (Rosi/Met, 4/1000 mg) reduced incident T2DM by 66% in subjects with impaired glucose tolerance. For insight on the hepatic effects of this therapy in relation to T2DM, we evaluated the temporal changes in waist, hepatic insulin sensitivity (1/Homeostasis Model Assessment of Insulin Resistance) and ALT in the Rosi/Met (n = 103) and placebo (n = 104) arms over median of 3.9 years. Waist did not differ between the arms. Hepatic insulin sensitivity improved in the Rosi/Met arm in year 1, but deteriorated thereafter as in the placebo arm. In contrast, Rosi/Met lowered ALT in year 1 and maintained this effect throughout the trial. Thus, low-dose Rosi/Met had no effect on central obesity, a transient effect on hepatic insulin sensitivity, and a sustained effect on ALT.

Utility of non-high-density lipoprotein cholesterol in assessing incident type 2 diabetes risk.

AIMS: Traditional lipid indices have been associated with type 2 diabetes, but limited data are available regarding non-high-density lipoprotein (non-HDL) cholesterol. In view of recent guidelines for the clinical management of dyslipidemia recommending the monitoring of non-HDL cholesterol as a secondary target after achieving the low-density lipoprotein (LDL) cholesterol goal, we aimed to assess the association of non-HDL cholesterol with incident type 2 diabetes and compare its utility as a risk predictor with traditional lipid variables in Aboriginal Canadians. METHODS: Of 606 diabetes-free participants at baseline, 540 (89.1%) returned for 10-year follow-up assessments. Baseline anthropometry, blood pressure, fasting insulin and serum lipids were measured. Fasting and 2-h postload glucose were obtained at baseline and follow-up to determine the incidence of type 2 diabetes. RESULTS: The cumulative incidence of type 2 diabetes was 17.5%. Higher non-HDL cholesterol, total-to-HDL cholesterol ratio, apolipoprotein B, triglyceride and LDL cholesterol and lower HDL cholesterol concentrations were individually associated with incident type 2 diabetes in univariate analyses (all p < 0.05). Non-HDL cholesterol was a superior determinant of incident diabetes compared with LDL cholesterol (comparing C-statistics of univariate models p = 0.01) or HDL cholesterol (p = 0.004). With multivariate adjustment including waist circumference, non-HDL cholesterol remained associated with incident diabetes [odds ratio (OR) 1.42 (95% confidence interval, CI 1.07-1.88)], while LDL cholesterol and HDL cholesterol became non-significant. CONCLUSIONS: Non-HDL cholesterol was associated with incident type 2 diabetes and was superior to LDL cholesterol as a risk predictor in this population. Further studies are required to establish the utility of non-HDL cholesterol in non-Aboriginal populations.

2022 update to the position statement by Primary Care Diabetes Europe: a disease state approach to the pharmacological management of type 2 diabetes in primary care.

Type 2 diabetes and its associated comorbidities are growing more prevalent, and the complexity of optimising glycaemic control is increasing, especially on the frontlines of patient care. In many countries, most patients with type 2 diabetes are managed in a primary care setting. However, primary healthcare professionals face the challenge of the growing plethora of available treatment options for managing hyperglycaemia, leading to difficultly in making treatment decisions and contributing to treatment and therapeutic inertia. This position statement offers a simple and patient-centred clinical decision-making model with practical treatment recommendations that can be widely implemented by primary care clinicians worldwide through shared-decision conversations with their patients. It highlights the importance of managing cardiovascular disease and elevated cardiovascular risk in people with type 2 diabetes and aims to provide innovative risk stratification and treatment strategies that connect patients with the most effective care.

A disease state approach to the pharmacological management of Type 2 diabetes in primary care: A position statement by Primary Care Diabetes Europe.

Type 2 diabetes and its associated comorbidities are growing more prevalent, and the complexity of optimising glycaemic control is increasing, especially on the frontlines of patient care. In many countries, most patients with type 2 diabetes are managed in a primary care setting. However, primary healthcare professionals face the challenge of the growing plethora of available treatment options for managing hyperglycaemia, leading to difficultly in making treatment decisions and contributing to therapeutic inertia. This position statement offers a simple and patient-centred clinical decision-making model with practical treatment recommendations that can be widely implemented by primary care clinicians worldwide through shared-decision conversations with their patients. It highlights the importance of managing cardiovascular disease and elevated cardiovascular risk in people with type 2 diabetes and aims to provide innovative risk stratification and treatment strategies that connect patients with the most effective care.

Impact on guidelines: The general practitioner point of view.

Primary care physicians are uniquely placed to offer holistic, patient-centred care to patients with T2DM. While the recent FDA-mandated cardiovascular outcome trials offer a wealth of data to inform treatment discussions, they have also contributed to increasing complexity in treatment decisions, and in the guidelines that seek to assist in making these decisions. To assist physicians in avoiding treatment inertia, Primary Care Diabetes Europe has formulated a position statement that summarises our current understanding of the available T2DM treatment options in various patient populations. New data from recent outcomes trials is contextualised and summarised for the primary care physician. This consensus paper also proposes a unique and simple tool to stratify patients into 'very high' and 'high' cardiovascular risk categories and outlines treatment recommendations for patients with atherosclerotic cardiovascular disease, heart failure and chronic kidney disease. Special consideration is given to elderly/frail patients and those with obesity. A visual patient assessment tool is provided, and a comprehensive set of prescribing tips is presented for all available classes of glucose-lowering therapies. This position statement will complement the already available, often specialist-focused, T2DM treatment guidelines and provide greater direction in how the wealth of outcome trial data can be applied to everyday practice.

The significance of extensor tendon tethering and dorsal joint capsule tightening after injury to the hand.

This paper examines the clinical problem of extensor tendon tethering and/or dorsal joint capsule tightening secondary to hand injury. One hundred and forty-one patients were examined 13 to 51 months after hand injuries of varying severity. Fifty-six patients (40%) had suffered simple and eighty-five patients (60%) complex injuries. Seventy-four (52%) of the 141 patients had no extensor tendon tethering and/or dorsal joint capsule tightening. In 30 (21%), the extensor tendon tethering and/or dorsal joint capsule tightening was considered to be "obvious" in that it was easily seen on examination using various commonly used clinical tests of finger flexion and extension. In 37 (26%), the extensor tendon tethering and/or dorsal joint capsule tightening was considered to be of "lesser degree" because it was only evident on application of specific tests which are described in this paper. Of the 37, 21 (56%) described themselves as being unable to make a "proper" fist with the injured hand, 33 (89%) had pain or discomfort on the dorsum of the injured hand and/or fingers on gripping (P < 0.01) and 25 (70%) had weakness of power of gripping (P < 0.01). Thirty-two (87%) complained of functional problems at work, with activities of daily living or with the pursuit of their hobbies.

The results of immediate re-repair of zone 1 and 2 primary flexor tendon repairs which rupture.

This study reports the outcome of immediate re-repair of primary flexor tendon repairs in zones 1 and 2 of the fingers which had ruptured. Between June 1989 and May 2003, a total of 62 fingers in 61 patients presented with ruptured flexor tendon repairs within 48 hours from rupture. Immediate re-repair and rehabilitation was carried out in 44 fingers (71%) in 43 (70%) patients. Thirty-six patients completed the 8-week therapy programme after re-repair in 37 fingers. Nine (24%) had excellent, 10 (27%) good, 5 (14%) fair and 13 (35%) had poor results when assessed by the original Strickland method. Five fingers in five patients ruptured the re-repair. Poor results and second ruptures were particularly common after re-repair of ruptured tendon repairs in the little finger. In the light of these findings, a policy for dealing with ruptured primary flexor tendon repairs in the fingers is suggested.

Correlation of cytotoxicity and mitotic spindle dissolution by vinblastine in mammalian cells.

In two hamster cell lines that differed 100-fold in their vinblastine sensitivity, dissolution of the mitotic spindle by vinblastine in living cells correlated with cytotoxicity from vinblastine expressed as suppression of colony formation. The effect on the spindle apparatus occurred in 30 sec or less and thus provides a rapid assay for determining the cytotoxic effects of the Vinca alkaloids, as well as the potential for quantitative assay of solutions of Vinca derivatives.

Physical activity, physical fitness, and insulin and glucose concentrations in an isolated Native Canadian population experiencing rapid lifestyle change.

OBJECTIVE: Little is known about the relation of physical activity and physical fitness to insulin resistance and glucose intolerance in isolated subarctic Native Canadian populations. The purpose of this effort was to examine the relation between activity and fitness and obesity and glucose concentrations in such a unique population. RESEARCH DESIGN AND METHODS: This study describes 530 men and women from the community of Sandy Lake, Ontario, located in the boreal forest region of central Canada. Fasting blood glucose and insulin concentrations were determined after an overnight fast. Past year physical activity levels were assessed using a modified version of an interviewer-administered questionnaire. Maximal oxygen uptake, a measure of cardiovascular fitness, was estimated using a submaximal step test. RESULTS: Total (leisure and occupational) physical activity and physical fitness were significantly associated with fasting insulin concentrations after adjusting for age, BMI or percent body fat, waist circumference, and fasting glucose concentration in men but not in women. The relations between physical activity, fitness, and fasting glucose concentrations were not as strong or as consistent as they were when fasting insulin concentration was the dependent variable. CONCLUSIONS: In this isolated Native Canadian community, both physical activity and fitness were independently associated with fasting insulin concentrations, suggesting a beneficial role of physical activity/fitness on insulin sensitivity that is separate from any influence of activity on body composition. The fact that this relation was found in men but not in women is most likely explained by issues related to the measurement of activity and fitness in this study and the fact that the women in this population appear to be less active than the men.

Serum immunoreactive leptin concentrations in a Canadian aboriginal population with high rates of NIDDM.

OBJECTIVE: To better understand the relationship between leptin and the anthropometric and physiological variables associated with diabetes, we measured this protein in an isolated Canadian aboriginal population with very high rates of NIDDM. RESEARCH DESIGN AND METHODS: There were 728 individuals aged 10-79 years who participated in a population-based survey to determine the prevalence of NIDDM and its associated risk factors. Fasting blood samples for glucose, insulin, triglyceride, and leptin were collected; a 75-g oral glucose tolerance test was administered and a second blood sample drawn after 120 min. Height, weight, and waist and hip circumference were determined, and percent body fat was estimated using biological impedance analysis. Fitness level was assessed in a subsample of individuals using a validated submaximal step test. The relationship between serum leptin and the other variables was assessed using Spearman's correlation coefficients and multiple linear regression. RESULTS: Serum leptin concentration was strongly correlated with adiposity, and levels were substantially higher in female subjects in all age-groups. For male subjects, percent body fat, fasting insulin level, and waist circumference were significant independent predictors of log serum leptin concentration in a multiple linear regression model (R2 = 0.582). For female subjects, these variables plus glucose tolerance status were included in the final model (R2 = 0.633). Fitness level, when included with the main effects of the above models, was a significant predictor for male subjects only. CONCLUSIONS: In an isolated aboriginal community with high rates of diabetes, we found significant independent relationships between leptin and percent body fat and between leptin and fasting insulin. As documented in other populations, the higher leptin concentration among female subjects may reflect differential leptin production from different adipose tissue beds, or leptin resistance. Independent relationships also existed among leptin and glucose tolerance status in female subjects and fitness level in male subjects.

The epidemiology of diabetes in pregnant Native Canadians. A risk profile.

OBJECTIVE: The purpose of this study was to determine the prevalence of diabetes in pregnancy (gestational diabetes mellitus [GDM] and NIDDM) and to identify risk factors in the development of GDM in a native population in northwestern Ontario, Canada. RESEARCH DESIGN AND METHODS: A retrospective analysis of 1,305 singleton deliveries among Ojibwa-Cree women from northwestern Ontario, Canada, was conducted from 1990 to 1993 inclusive. GDM was diagnosed using a 3-h oral glucose tolerance test (OGTT) and defined according to standard guidelines. RESULTS: The overall prevalence of diabetes in pregnancy (NIDDM and GDM) was 11.6% (152 of 1,305) with a GDM prevalence of 8.4% (110 of 1,305). Among 741 women with complete data, prevalence rates increased with age, peaking at 46.9% in the age-group > or = 35 years. Significant risk factors for GDM included older maternal age, multiparity, prepregnancy obesity, a family history of diabetes, and a history of GDM in previous pregnancies. CONCLUSIONS: Diabetes in pregnancy among Ojibwa-Cree reported here represent the highest rates reported to date in a Canadian population. The high rates of maternal obesity and relative young age of this population further highlight the urgent need for diabetes screening and prevention in this population.

Clinical utility of HNF1A genotyping for diabetes in aboriginal Canadians.

OBJECTIVE: To determine the diagnostic performance characteristics of HNF1A genotyping for diabetes and impaired glucose tolerance (IGT) in Canadian Oji-Cree Indians. RESEARCH DESIGN AND METHODS: We studied all Oji-Cree subjects > or = 50 years of age (96 subjects) who had participated in a community-wide prevalence survey for type 2 diabetes. Subjects were classified either as having "disease," which included type 2 diabetes and IGT, or not. All subjects were genotyped for the HNF1A G319S mutation. RESULTS: The prevalence of disease in this group was 65.7%, of whom 71.4% had type 2 diabetes. For a carrier of HNF1A S319, the specificity, sensitivity, and positive and negative predictive values were 97.0, 30.1, 95.0, and 42.1%, respectively. When the pretest disease prevalence was accounted for, the probability of disease after a positive test was 97.2%, and the probability of disease after a negative test was 42.2%. The values were very similar for the subgroup of subjects with type 2 diabetes alone. CONCLUSIONS: The HNF1A genotype appears to be the most specific genetic test yet reported for the prediction of a common multifactorial disease by applying present-day standards of clinical epidemiology in molecular genetics. A positive test result had particular diagnostic value in the Oji-Cree: a subject with HNF1A S319 was virtually certain of having diabetes or IGT by 50 years of age. In contrast, a subject without HNF1A S319 had a reduced risk compared with the age-specific prevalence but was not totally risk-free. Because HNF1A S319 was not the only predisposing factor for diabetes in the Oji-Cree, subjects without HNF1A S319 were still at some risk for diabetes or IGT.

Absence of association between genetic variation of the beta 3-adrenergic receptor and metabolic phenotypes in Oji-Cree.

OBJECTIVE: To assess the association between the common missense variant, Y64R, in the gene encoding the beta 3-adrenergic receptor, ADRB3, and intermediate phenotypes related to obesity and NIDDM in Canadian Oji-Cree. RESEARCH DESIGN AND METHODS: We determined genotypes of the ADRB3 Y64R polymorphism in 508 clinically and biochemically well-characterized adult Oji-Cree, of whom 115 had NIDDM. We tested for associations with multivariate analysis of variance. RESULTS: We found the ADRB3 R64 allele frequency to be 0.40 in this population, which is the highest yet observed in a human population. Furthermore, 15% of subjects were R64/R64 homozygotes, compared with a virtual absence of homozygotes in European study samples. However, we found no statistically significant associations of the ADRB3 Y64R genotype either with the presence of NIDDM, with indexes of obesity, or with intermediate quantitative biochemical traits related to NIDDM. CONCLUSIONS: Despite the very high frequency of the ADRB3 R64 allele in this sample of aboriginal people, it was not associated with any metabolic phenotype. This suggests that the ADRB3 R64 allele is probably not a major determinant of obesity or NIDDM in these aboriginal Canadians.

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.

Cross-sectional and prospective associations between proinsulin and cardiovascular disease risk factors in a population experiencing rapid cultural transition.

OBJECTIVE: To examine cross-sectional and prospective associations between proinsulin and cardiovascular disease risk factors using data from a population-based study of type 2 diabetes among Native Canadians. RESEARCH DESIGN AND METHODS: Between 1993 and 1995, 72% of eligible members of a Native Canadian community participated in a baseline diabetes prevalence survey. Fasting samples were collected for glucose, C-peptide, proinsulin, lipids, and apolipoproteins. A 75-g oral glucose tolerance test was administered, and a second sample for glucose was drawn after 120 min. Blood pressure and waist circumference were determined. In the present study, subjects with normal glucose tolerance (NGT) (n = 505) and impaired glucose tolerance (IGT) (n = 74) were included in cross-sectional analyses. In 1998, 95 individuals who had IGT or NGT at baseline with an elevated 2-h glucose concentration (> or = 7.0 mmol/l) participated in a follow-up evaluation using the protocol used at baseline. Cross-sectional and prospective associations between proinsulin and cardiovascular risk factors were assessed using correlation and multiple linear regression analyses. RESULTS: After adjustment for covariates including age, sex, C-peptide, waist circumference, and glucose tolerance status, fasting proinsulin concentration was significantly associated with concurrently measured lipid and apolipoprotein concentrations (triglycerides: r = 0.18, P < 0.0001; total cholesterol: r = 0.10, P = 0.02; LDL cholesterol: r = 0.11, P = 0.01; HDL cholesterol: r = -0.16, P = 0.0002; apolipoprotein (apo) B: r = 0.17, P < 0.0001; apoAI: r = -0.11, P = 0.008). In the adjusted prospective analysis, baseline triglycerides, HDL cholesterol, and apoB were associated with changes over time in proinsulin (r = 0.23, P = 0.04; r = -0.30, P = 0.01; r = 0.23, P = 0.04; respectively). CONCLUSIONS: These results confirm previously reported cross-sectional associations between proinsulin and lipid concentrations. In addition, an unexpected association between baseline lipids and proinsulin change was documented.

Genetic variation in LMNA modulates plasma leptin and indices of obesity in aboriginal Canadians.

We previously showed that a rare mutation in LMNA, which encodes lamins A and C, underlies autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD). Because FPLD is an extreme example of genetically disturbed adipocyte differentiation, it is possible that common variation in LMNA is associated with obesity-related phenotypes. We therefore analyzed the relationships between the common LMNA 1908T/C single nucleotide polymorphism (SNP) and plasma leptin and anthropometric indices in 306 nondiabetic Canadian Oji-Cree. We found that subjects with the LMNA 1908T/1908T genotype had significantly higher plasma leptin than the subjects with either the 1908C/1908T or 1908C/1908C genotypes, after adjustment for age and sex. Physical indices of obesity, such as body mass index, percent body fat, and ratio of waist-to-hip circumference, were also higher among Oji-Cree subjects with the LMNA 1908T/1908T genotype than the subjects with either the 1908C/1908T or 1908C/1908C genotypes. The results suggest that common genetic variation in LMNA may be an important determinant of plasma leptin and obesity-related quantitative traits.