Prospective association between late evening food consumption and risk of prediabetes and diabetes: the Whitehall II cohort study.

AIMS: We examined whether late evening food consumption was prospectively associated with the risk of developing prediabetes or diabetes in a large observational study of individuals with normoglycaemia. METHODS: Participants were 2642 men and women with normoglycaemia (HbA1c < 39 mmol/mol; < 5.7%) from the Whitehall II study. Time of last eating episode (TLEE) before the examination day was assessed at baseline. We studied the associations of TLEE with 5-year changes in HbA1c and risk of developing prediabetes or diabetes (HbA1c ≥ 39 mmol/mol; ≥ 5.7%). Potential heterogeneity in the association between TLEE and prediabetes or diabetes was examined using recursive partitioning modelling for time-to-event outcomes. RESULTS: There was a tendency of an overall association of TLEE with change in HbA1c but with little effect size [ß per 1-h increase in TLEE = 0.2 mmol/mol, 95% CI -0.0 to 0.3 (0.01%, -0.00 to 0.03); P = 0.055] and no association with the risk of developing prediabetes/diabetes (risk ratio per 1-h increase in TLEE = 1.03, 95% CI 0.94 to 1.13; P = 0.511). According to the recursive partitioning modelling, women with HbA1c ≤ 36 mmol/mol and TLEE after 21:00 had a 1.51 times (95% CI 1.16 to 1.93) higher 5-year risk of developing prediabetes or diabetes than those having their TLEE between 16:00 and 21:00 (35.4% vs. 23.5%; P = 0.003). CONCLUSIONS: There was no overall association of TLEE with the development of prediabetes or diabetes in the Whitehall II population. However, explorative analyses suggested that eating late in the evening was associated with increased risk of developing prediabetes/diabetes among women with good glycaemic control. Whether restricting late evening food consumption is effective and feasible for the prevention of Type 2 diabetes needs testing in randomized controlled trials.

Barriers to and motivators for physical activity among people with Type 2 diabetes: patients' perspectives.

AIM: To explore barriers to and motivators for physical activity in a group of overweight and obese individuals with dysregulated Type 2 diabetes. METHODS: Data were collected from the Steno Diabetes Center's outpatient clinic in Denmark. Four focus groups were conducted including 28 individuals with Type 2 diabetes aged 39-71 years. The facilitators used open-ended questions and probes such as images, statements and quotations about physical activity to foster active participation and interaction among participants. Focus groups were recorded on video and the discussions were transcribed and analysed thematically. RESULTS: We identified four main themes: 1) the body as a barrier to physical activity because of functional limitations; 2) logistical challenges, including lack of time and awareness of where to exercise in the local area; 3) being physically active with others, providing a sense of mutual commitment and enjoyment; and 4) goal-setting and self-tracking, which was seen as an opportunity to track physical improvement over time. CONCLUSIONS: The findings suggest that, once people are active, a high level of social interaction may help maintain their activity levels. Further research is needed to investigate the effect of combining individually tailored exercise plans with the establishment of customized and locally based exercise communities that offer enjoyment and support. Additionally, it is relevant to explore experiences of using self-tracking technologies to review short- and long-term goals.

Intensive multifactorial treatment modifies the effect of family history of diabetes on glycaemic control in people with Type 2 diabetes: a post hoc analysis of the ADDITION-Denmark randomized controlled trial.

AIM: To investigate whether intensive multifactorial treatment can reverse the predisposed adverse phenotype of people with Type 2 diabetes who have a family history of diabetes. METHODS: Data from the randomized controlled trial ADDITION-Denmark were used. A total of 1441 newly diagnosed patients with diabetes (598 with family history of diabetes) were randomized to intensive treatment or routine care. Family history of diabetes was defined as having one parent and/or sibling with diabetes. Linear mixed-effects models were used to assess the changes in risk factors (BMI, waist circumference, blood pressure, lipids and HbA1c ) after 5 years of follow-up in participants with and without a family history of diabetes. An interaction term between family history of diabetes and treatment group was included in the models to test for a modifying effect of the intervention. All analyses were adjusted for age, sex, baseline value of the risk factor and general practice (random effect). RESULTS: At baseline, participants with a family history of diabetes were younger and had a 1.1 mmol/mol (0.1%) higher HbA1c concentration at the time of diagnosis than those without a family history of diabetes. Family history of diabetes modified the effect of the intervention on changes in HbA1c levels. In the group receiving routine care, participants with a family history of diabetes experienced an improvement in HbA1c concentration that was 3.3 mmol/mol (0.3%) lower than the improvement found in those without a family history of diabetes after 5 years of follow-up. In the intensive treatment group, however, there was no difference in HbA1c concentrations between participants with and without a family history of diabetes after 5 years of treatment. CONCLUSIONS: Intensive treatment of diabetes may partly remove the adverse effects of family history of diabetes on glycaemic control. The effect of this improvement on long-term diabetic complications warrants further investigation.

Effects of 12 weeks of treatment with fermented milk on blood pressure, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind placebo-controlled study.

OBJECTIVE: Studies have indicated a blood pressure (BP)-lowering effect of milk-derived peptides in non-diabetic individuals, but the cardiometabolic effects of such peptides in patients with type 2 diabetes (T2D) are not known. We investigated the effect of milk fermented with Lactobacillus helveticus on BP, glycaemic control and cardiovascular risk factors in T2D. DESIGN: A randomised, double-blinded, prospective, placebo-controlled study. METHODS: In one arm of a factorial study design, 41 patients with T2D were randomised to receive 300 ml milk fermented with L. helveticus (Cardi04 yogurt) (n=23) or 300 ml artificially acidified milk (placebo yogurt) (n=18) for 12 weeks. BPs were measured over 24-h, and blood samples were collected in the fasting state and during a meal test before and after the intervention. RESULTS: Cardi04 yogurt did not reduce 24-h, daytime or nighttime systolic or diastolic BPs compared with placebo (P>0.05). Daytime and 24-h heart rate (HR) were significantly reduced in the group treated by Cardi04 yogurt compared with the placebo group (P<0.05 for both). There were no differences in HbA1c, plasma lipids, C-reactive protein, plasminogen activator inhibitor-1, tumour necrosis factor alpha, tissue-type plasminogen activator: Ag, and von Willebrand factor: Ag between the groups. The change in fasting blood glucose concentration differed significantly between the two groups with a larger increase in the placebo group (P<0.05). CONCLUSIONS: Ingestion of milk fermented with L. helveticus compared with placebo for 12 weeks did not significantly reduce BP in patients with T2D. Our finding of lower HRs and fasting plasma glucose levels in T2D patients during ingestion of fermented milk needs further validation.

Insulin resistance and beta-cell function in different ethnic groups in Kenya: the role of abdominal fat distribution.

Little is known about the pathophysiology of diabetes in Africans. Thus, we assessed whether insulin resistance and beta-cell function differed by ethnicity in Kenya and whether differences were modified by abdominal fat distribution. A cross-sectional study in 1,087 rural Luo (n = 361), Kamba (n = 378), and Maasai (n = 348) was conducted. All participants had a standard 75-g oral glucose tolerance test (OGTT). Venous blood samples were collected at 0, 30, and 120 min. Serum insulin was analysed at 0 and 30 min. From the OGTT, we assessed the homoeostasis model assessment of insulin resistance by computer model, early phase insulin secretion, and disposition index (DI) dividing insulin secretion by insulin resistance. Abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) thickness were carried out by ultrasonography. Linear regression analyses were done to assess ethnic differences in insulin indices. The Maasai had 32 and 17% higher insulin resistance than the Luo and Kamba, respectively (p < 0.001). Early phase insulin secretion was 16% higher in the Maasai compared to the Luo (p < 0.001). DI was 12% (p = 0.002) and 10% (p = 0.015) lower in the Maasai compared to the Luo and Kamba, respectively. Adjustments of SAT (range 0.1-7.1 cm) and VAT (range 1.5-14.2 cm) largely explained these inter-group differences with the Maasai having the highest combined abdominal fat accumulation. The Maasai had the highest insulin resistance and secretion, but the lowest relative beta-cell function compared to the Luo and Kamba. These differences were primarily explained by abdominal fat distribution.

Reduced incidence of lower-extremity amputations in a Danish diabetes population from 2000 to 2011.

AIMS: Diabetic foot disease and amputations severely reduce quality of life and have major economic consequences. The aim of this study was to estimate time trends in the incidence of lower-extremity amputations in Danish people with diabetes. METHODS: We studied major and minor lower-extremity amputations from 2000 to 2011 among 11,332 people with diabetes from the Steno Diabetes Center. Amputations were identified by linkage of the electronic medical system with the National Patient Registry. Sex-specific incidence rates of amputations by age, diabetes duration, calendar time and diabetes type were modelled by Poisson regression. RESULTS: From 2000 to 2011, 384 incident lower-extremity amputations (205 major, 179 minor) occurred during 100,495 years of patient follow-up. From 2000 to 2011, the incidence of all lower-extremity amputations decreased by 87.5% among men and 47.4% among women with type 1 diabetes and by 83.3% among men and 79.1% among women with type 2 diabetes (P < 0.001). In particular, there was a decline in major lower-extremity amputations. In 2011, the incidence rates of major lower-extremity amputations were 0.25 (95% CI 0.07-0.82) among men and 0.21 (95% CI 0.06-0.71) among women per 1000 patient-years at age 50 years and 0.56 (95% CI 0.18-1.89) among men and 0.41 (95% CI 0.16-1.09) among women per 1000 patient-years at age 70 years. No significant change in incidence of minor amputations was observed. CONCLUSION: The incidence of major lower-extremity amputations reduced significantly from 2000 to 2011 in Danish people with diabetes followed at a diabetes specialist centre.

Effects of 12 weeks' treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study.

AIMS/HYPOTHESIS: Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA(1c) and cardiovascular risk factors in type 2 diabetes. METHODS: Forty-one patients with type 2 diabetes using dietary control or oral glucose-lowering treatment were randomised to receive add-on esomeprazole 40 mg (n = 20) or placebo (n = 21) for 12 weeks. Randomisation was carried out prior to inclusion on the basis of a computer-generated random-number list. The allocation sequence was concealed in sealed envelopes from the researcher enrolling and assessing participants. The study was undertaken at Steno Diabetes Center, Gentofte, Denmark. The primary outcome was change in AUC for insulin levels during a meal test. Secondary outcomes were the levels of HbA(1c) and biochemical markers of cardiovascular risk, including lipids, coagulation factors, inflammation markers, markers of endothelial function and 24 h ambulatory BP measurements. RESULTS: Forty-one participants were analysed. In the esomeprazole-treated group the AUC for insulin did not change (before vs after treatment: 28,049 ± 17,659 vs 27,270 ± 32,004 pmol/l × min (p = 0.838). In the placebo group AUC for insulin decreased from 27,392 ± 14,348 pmol/l × min to 22,938 ± 11,936 pmol/l × min (p = 0.002). Esomeprazole treatment (n = 20) caused a ninefold increase in the AUC for gastrin. HbA(1c) increased from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.3 ± 0.8% (56 ± 6 mmol/mol) in the esomeprazole-treated group and from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.4 ± 0.8% (57 ± 6 mmol/mol) in the placebo group (n = 21) (p for difference in change >0.05). Except for BP, there were no differences between the groups in the markers of cardiovascular risk (p > 0.05). Monitoring of 24 h ambulatory BP showed a significant decrease in daytime systolic BP, daytime diastolic BP and 24 h diastolic BP in the placebo group (p < 0.05). No change in BP was seen in the patients treated with esomeprazole. CONCLUSIONS/INTERPRETATION: Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.

Incretin and pancreatic hormone secretion in Caucasian non-diabetic carriers of the TCF7L2 rs7903146 risk T allele.

We characterised 62 non-diabetic, middle-aged, Caucasians with and without the T risk allele of rs7903146 in transcription factor 7-like 2 (TCF7L2) with regard to secretion of insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) as well as insulin sensitivity and endogenous glucose production. All participants had a 3-h oral glucose tolerance test (OGTT), an intravenous glucose tolerance test and a euglycaemic, hyperinsulinaemic clamp. After adjustment for age and sex, risk T allele carriers had higher haemoglobin A1c levels (p = 0.030), reduced first-phase insulin response (p = 0.048), higher peripheral insulin sensitivity (p = 0.050) and lower fasting GIP concentrations (p = 0.003) than CC allele carriers. The latter was also reflected by lower total GIP secretion during the OGTT (p = 0.018). We found no significant differences in endogenous glucose production, hepatic insulin sensitivity or fasting concentrations of glucose, insulin, glucagon and GLP-1 between the groups. The findings suggest that the effect of TCF7L2 on diabetes risk may include reduced secretion of GIP.

Effect of time of day and fasting duration on measures of glycaemia: analysis from the Whitehall II Study.

AIMS/HYPOTHESIS: We aimed to study diurnal variation in glucose regulation by examining the effects of time of day and fasting duration on fasting plasma glucose (FPG), 2 h post-load plasma glucose (2hPG) and HbA(1c) levels. METHODS: We analysed data from 5,978 non-diabetic white men and women from the prospective Whitehall II Study. All studied participants fasted for at least 8 h before a clinical examination, which included an OGTT and anthropometric measurements. We fitted mixed-effects models for FPG, 2hPG and HbA(1c) as outcome variables, and time of day and/or fasting duration as explanatory variables. Models were adjusted for age, BMI and study phase. RESULTS: Time of day and fasting duration were associated inversely with FPG and positively with 2hPG. The mean difference between measures at 08:00 and 15:00 hours in men/women was -0.46 (95% CI -0.50, -0.42) mmol/l/-0.39 (95% CI -0.46, -0.31) mmol/l and 1.39 (95% CI 1.25, 1.52) mmol/l/1.19 (95% CI 0.96, 1.42) mmol/l for FPG and 2hPG, respectively. HbA(1c) levels were independent of either time. Time of day and fasting duration were independently associated with 2hPG. In contrast, the effect of fasting duration on FPG was markedly attenuated with adjustment for time of day. Ageing, but not obesity, was associated with increased diurnal variation in glucose tolerance. CONCLUSIONS/INTERPRETATION: Both time of day and fasting duration should be considered in clinical practice and epidemiological studies, since they have clinically relevant effects on FPG and 2hPG levels. As biochemically expected, HbA(1c) levels are independent of time of blood sampling and fasting duration.

Estimating insulin sensitivity and beta cell function: perspectives from the modern pandemics of obesity and type 2 diabetes.

The 1985 manuscript describing the HOMA model, by Matthews and colleagues, is the most cited paper in the history of Diabetologia. In this edition of 'Then and now' we assess the impact of this seminal paper by considering the contribution of this elegant work in the context of the most rapidly changing period in the history of diabetes. HOMA was born in the middle of an 'era' of insulin resistance, and was subsequently nurtured and grew during the 'eras' of insulin sensitisers and diabetes prevention. From the modern era of insulin resistance onward, researchers have sought a convenient method for measuring insulin sensitivity and secretion, and found this in HOMA. However, the explosion in the prevalence of diabetes clearly underlines that an understanding of insulin resistance and how it can be measured has been insufficient to make any impact on the growing pandemic of diabetes. Knowledge of individual physiology is important, but the dramatic impact of the modern environment may be the factor that has escaped attention until very recently. An optimist can only state that the coming 'era' in diabetes research will be a period of true translation of scientific insight and implementation of effective disease prevention.

Low birthweight and premature birth are both associated with type 2 diabetes in a random sample of middle-aged Danes.

AIMS/HYPOTHESIS: We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237). METHODS: Information about size at birth and prematurity was identified from original midwife records in 4,744 middle-aged Danes. Type 2 diabetes status, insulin sensitivity (Matsuda index) and beta cell function (disposition index) were assessed using a 75 g oral glucose tolerance test. Participants born prematurely were compared with a group of at-term participants born small for gestational age. RESULTS: An increase in birthweight of 1 kg was associated with a 51% (OR 0.49, 95% CI 0.35-0.69) reduced risk of type 2 diabetes. Ponderal index, reflecting thinness at birth, was associated with type 2 diabetes to the same extent as birthweight. The prevalence of type 2 diabetes was increased to a similar degree in participants born prematurely and participants born small for gestational age, although the former had a higher ponderal index at birth. In addition, birthweight z-scores, reflecting fetal growth rate, were unrelated to the risk of type 2 diabetes and to other measures of glucose regulation in participants born prematurely. While low birthweight was inversely associated with insulin sensitivity and beta cell function, prematurity was associated solely with decreased insulin sensitivity. CONCLUSIONS/INTERPRETATION: While the association between birthweight and risk of type 2 diabetes is mediated via combined effects on beta cell function and insulin sensitivity, prematurity seems to influence risk of type 2 diabetes via attenuated insulin sensitivity only and independently of fetal growth rates.

Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men.

Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) gene. Subjects were reexamined after 4 wk of retraining. We found that bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after 4 wk of retraining. Pathway analyses revealed significant downregulation of 34 pathways, predominantly those of genes associated with mitochondrial function, including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin stimulation in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. We conclude that impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after 4 wk of retraining underscores the importance of maintaining a minimum of daily physical activity.

Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight.

AIMS/HYPOTHESIS: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. METHODS: Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. RESULTS: Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (beta = -33 g [95% CI -55, -10], p = 0.004) and CDKAL1 rs7756992 (beta = -22 g [95% CI -43, -1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (beta = -20 g [95% CI -29, -11], p = 5 x 10(-6)). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (beta = -16 g [95% CI -24, -8], p = 8 x 10(-5)). On average, individuals with high genetic risk (>or=25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (beta = -35 g [95% CI -69, -2], p = 0.037). CONCLUSIONS/INTERPRETATION: We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.

Sex differences in glucose levels: a consequence of physiology or methodological convenience? The Inter99 study.

AIMS/HYPOTHESIS: We aimed to examine whether sex differences in fasting plasma glucose (FPG), 2 h post-OGTT plasma glucose (2hPG) and HbA(1c) could be explained by differences in body size and/or body composition between men and women in a general non-diabetic Danish population. Moreover, we aimed to study to what degree the newly suggested high-risk HbA(1c) criteria overlapped with the current OGTT-based criteria of glucose intolerance. METHODS: We used cross-sectional data from 6,006 non-diabetic men and women. HbA(1c) and FPG levels were measured and a 75 g OGTT was performed in all individuals. Height, weight and waist and hip circumferences were measured and BMI was calculated. Data were analysed in age-adjusted linear regression models. RESULTS: Men had higher FPG and HbA(1c) levels than women, and women had higher 2hPG levels than men. Sex differences in 2hPG levels were explained by differences in height and FPG levels, but sex differences in FPG or HbA(1c) levels were not explained by anthropometric measures. Among individuals with HbA(1c) in the high-risk range (6.0-6.5%), 73% had normal glucose tolerance. CONCLUSIONS/INTERPRETATION: Sex differences in 2hPG levels after an OGTT may to some extent be a consequence of giving the same amount of glucose to individuals with different body size. In contrast, sex differences in FPG and HbA(1c) levels are likely to have a true physiological basis. In clinical practice, the HbA(1c) assay may be more convenient than the OGTT, but it is important to note that different populations are identified by the two methods.

The disposition index: adjustment for peripheral vs. hepatic insulin sensitivity?

The assessment of pancreatic beta cell function in humans is challenging because of a complex interplay between insulin secretion, insulin sensitivity and hepatic insulin extraction. Simplified, the relationship between insulin secretion and insulin sensitivity can be described by an approximate hyperbola with the product of the two variables being constant for individuals with the same degree of glucose tolerance (the disposition index). Strengths and limitations of the disposition index have been widely debated in the literature. In this review we will focus on another and until recently unrecognized dimension of the disposition index, namely the issue of adjusting insulin secretion for hepatic versus peripheral insulin sensitivity. An underlying assumption of this issue is that the liver as compared to muscle plays a different role in the regulation of in vivo insulin secretion.

Impact of size at birth and prematurity on adult anthropometry in 4744 middle-aged Danes - The Inter99 study.

Low birth weight is related to increased risk of developing cardiovascular disease and type 2 diabetes in adult life. Since obesity is closely associated with type 2 diabetes and cardiovascular disease, the relationship between size at birth and adult anthropometry is of interest as a mediator of the relationship between birth weight and metabolic diseases. The aim of this study was, therefore, to examine the effect of size at birth and prematurity on measures of adult anthropometry taking adult socio-economic status and lifestyle variables into account. Midwife records with information on mother's age and parity as well as weight, length and maturity at birth were traced in 4744 Danes born between 1939 and 1970. Measures of adult anthropometry (weight, height, body mass index (BMI), waist circumference, hip circumference and waist/hip ratio) had previously been recorded together with information on socio-economic factors, lifestyle and parental diabetes status. Mother's age, parity and diabetes status were associated with offspring birth weight. Size at birth was positively associated with adult height and weight, but only weakly associated with BMI and not associated with waist/hip ratio when adjusted for socio-economic and lifestyle factors. Infants born preterm were less growth restricted at birth and grew to be taller and heavier compared with term infants born small for gestational age. Altogether, this study does not find evidence that obesity or a central fat distribution is mediating the relationship between low birth weight and risk of cardiovascular disease or type 2 diabetes in later life.

A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads.

AIMS/HYPOTHESIS: An association between elevated fasting plasma glucose and the common rs560887 G allele in the G6PC2/ABCB11 locus has been reported. In Danes we aimed to examine rs560887 in relation to plasma glucose and serum insulin responses following oral and i.v. glucose loads and in relation to hepatic glucose production during a hyperinsulinaemic-euglycaemic clamp. Furthermore, we examined rs560887 for association with impaired fasting glycaemia (IFG), impaired glucose tolerance (IGT), type 2 diabetes and components of the metabolic syndrome. METHODS: rs560887 was genotyped in the Inter99 cohort (n = 5,899), in 366 young, healthy Danes, in non-diabetic relatives of type 2 diabetic patients (n = 196), and in young and elderly twins (n = 159). Participants underwent an OGTT, an IVGTT or a 2 h hyperinsulinaemic-euglycaemic clamp. RESULTS: The rs560887 G allele associated with elevated fasting plasma glucose (p = 2 x 10(-14)) but not with plasma glucose levels at 30 min (p = 0.9) or 120 min (p = 0.9) during an OGTT. G allele carriers had elevated levels of serum insulin at 30 min during an OGTT (p = 1 x 10(-4)) and relatives of type 2 diabetes patients carrying the G allele had an increased acute insulin response (p = 4 x 10(-4)) during an IVGTT. Among elderly twins, G allele carriers had higher basal hepatic glucose production (p = 0.04). Finally, the G allele associated with the risk of having IFG (OR 1.26, 95% CI 1.08-1.47, p = 0.002), but not with IGT (OR 0.94, 95% CI 0.82-1.08, p = 0.4) or type 2 diabetes (OR 0.93, 95% CI 0.84-1.04, p = 0.2). CONCLUSIONS/INTERPRETATION: The common rs560887 G allele in the G6PC2/ABCB11 locus is associated with increased fasting glycaemia and increased risk of IFG, associations that may be partly related to an increased basal hepatic glucose production rate.

Pathophysiology and aetiology of impaired fasting glycaemia and impaired glucose tolerance: does it matter for prevention and treatment of type 2 diabetes?

Prior to the development of type 2 diabetes, glucose levels increase into the prediabetic states of isolated impaired fasting glycaemia (i-IFG), isolated impaired glucose tolerance (i-IGT), or combined IFG/IGT. A better understanding of the aetiology and pathophysiology of the prediabetic states might give a basis for the development of individualised prevention and treatment strategies for type 2 diabetes. Several studies have examined mechanisms and potential aetiological factors leading to the development of the different prediabetic states. The pathophysiology of i-IFG seems to include the following key defects: reduced hepatic insulin sensitivity, stationary beta cell dysfunction and/or chronic low beta cell mass, altered glucagon-like peptide-1 secretion and inappropriately elevated glucagon secretion. Conversely, the prediabetic state i-IGT is characterised by reduced peripheral insulin sensitivity, near-normal hepatic insulin sensitivity, progressive loss of beta cell function, reduced secretion of glucose-dependent insulinotropic polypeptide and inappropriately elevated glucagon secretion. Individuals developing combined IFG/IGT exhibit severe defects in both peripheral and hepatic insulin sensitivity as well as a progressive loss of beta cell function. The aetiologies of i-IFG and i-IGT also seem to differ, with i-IFG being predominantly related to genetic factors, smoking and male sex, while i-IGT is predominantly related to physical inactivity, unhealthy diet and short stature. Since the transition from the prediabetic states to overt type 2 diabetes is characterised by a non-reversible vicious cycle that includes severe deleterious effects on glucose metabolism, there are good reasons to use the well-established aetiological and pathophysiological differences in i-IFG, i-IGT and IFG/IGT to design individualised preventive strategies.

Predictors of future fasting and 2-h post-OGTT plasma glucose levels in middle-aged men and women-the Inter99 study.

AIMS: Screening and prevention strategies for Type 2 diabetes require insight into the aetiological and potentially different risk factors leading to early impairments of fasting plasma glucose (FPG) and 2-h post-load plasma glucose (2hPG) levels. We studied whether risk factors predicting subtle elevations of FPG levels were different from those predicting elevations of 2hPG levels in men and women. METHODS: We used baseline and 5-year follow-up data from middle-aged men and women with normal glucose tolerance (NGT) at baseline in the Danish population-based Inter99 study (n = 3164). Anthropometric and non-anthropometric baseline predictors of the 5-year FPG and 2hPG levels were estimated in linear regression models stratified by gender. RESULTS: In men, but not in women, smoking and family history of diabetes predicted increased FPG levels, whereas high physical activity predicted a decline in 2hPG levels. Among the anthropometric variables, large waist circumference was the strongest predictor of increased FPG levels in men, whereas high body mass index (BMI) was the strongest predictor of increased FPG levels in women. In both men and women, BMI and waist circumference were equally strong in predicting 2hPG levels. Furthermore, short height predicted increased 2hPG levels in men, and short height and low hip circumference predicted increased 2hPG levels in women. CONCLUSIONS: Risk factors that predict future FPG levels are different from those predicting future 2hPG levels. Furthermore, different risk factors predict glycaemic levels in men compared with women. These findings indicate that different aetiological pathways may lead to Type 2 diabetes in men and women.