Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. METHODS: Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. CONCLUSIONS: Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.

The thrifty phenotype hypothesis revisited.

Twenty years ago, Hales and Barker along with their co-workers published some of their pioneering papers proposing the 'thrifty phenotype hypothesis' in Diabetologia (4;35:595-601 and 3;36:62-67). Their postulate that fetal programming could represent an important player in the origin of type 2 diabetes, the metabolic syndrome and cardiovascular disease (CVD) was met with great scepticism.More recently, their observations have been confirmed and expanded in many epidemiological and animal experimental studies, and human integrative physiological studies have provided insights into some of the underlying molecular mechanisms. Type 2 diabetes is a multiple-organ disease, and developmental programming, with its idea of organ plasticity, is a plausible hypothesis for a common basis for the widespread organ dysfunctions in type 2 diabetes and the metabolic syndrome. Only two among the 45 known type 2 diabetes susceptibility genes are associated with low birthweight, indicating that the association between low birthweight and type 2 diabetes is mainly non-genetic. Prevention programmes targeting adult lifestyle factors seems unable to stop the global propagation of type 2 diabetes, and intensive glucose control is inadequate to reduce the excess CVD mortality in type 2 diabetic patients. Today, the thrifty phenotype hypothesis has been established as a promising conceptual framework for a more sustainable intergenerational prevention of type 2 diabetes.

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men.

AIMS/HYPOTHESIS: We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. METHODS: We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action. RESULTS: Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function. CONCLUSIONS/INTERPRETATION: Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.

Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes.

BACKGROUND: In addition to its glucose-lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study, we report the effect of a 1-year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control. METHODS: One hundred T1DM patients with haemoglobinA(1c) (HbA(1c)) > or =8.5% during the year before enrolment entered a 1-month run-in period on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1000 mg twice daily) or placebo for 12 months (double masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. Outcomes were assessed at baseline and after 1 year. RESULTS: After 1 year, in those patients who did not start or stop statin therapy during the trial, metformin treatment significantly reduced total and LDL cholesterol by approximately 0.3 mmol/l compared with placebo (p = 0.021 and p = 0.018 respectively). Adjustment for statin use or known cardiovascular disease did not change conclusions. In statin users (metformin: n = 22, placebo: n = 13), metformin significantly lowered levels of LDL and non-HDL cholesterol by approximately 0.5 mmol/l compared with placebo (adjusted for changes in statin dose or agent: p = 0.048 and p = 0.033 respectively). HbA(1c) (previously reported) was not significant different between treatments. CONCLUSION: In patients with poorly controlled T1DM, at similar glycaemic levels, adjunct metformin therapy during 1 year significantly lowered levels of proatherogenic cholesterolaemia independent of statin therapy.

Being born small-for-gestational-age is associated with an unfavourable dietary intake in Danish adolescent girls: findings from the Danish National Birth Cohort.

Individuals born small have an increased risk for developing type 2 diabetes. Altered food preferences in these subjects seem to play a role; however, limited evidence is available on the association between being born small-for-gestational-age (SGA) at term and food intake in adolescence. Alterations in leptin, ghrelin and dopamine levels are suggested mechanisms linking SGA with later food intake. From a large prospective Danish National Birth Cohort, we compared dietary intake of adolescents being born SGA with normal-for-gestational-age (NGA) adolescents. Intake of foods and nutrients was assessed by a validated food frequency questionnaire in a subsample of 15,607 14-year-old individuals born at term. SGA was defined by birth weight (BW) <10th percentile (n = 1470) and NGA as BW between 10 and 90th percentile (n = 14,137) according to sex and gestational age-specific BW standard curves. Girls born SGA had a 7% (95% CI: 3-12%, P = 0.002) higher intake of added sugar and a 2-8% lower intake of dietary fibre, vegetables, polyunsaturated fatty acids, and total n-6, compared with NGA girls (P < 0.05). Adjusting for parental socio-occupational status, maternal smoking and diet in pregnancy did not substantially change the differences in dietary intake, except from dietary fibre, which were no longer statistically significant. No significant differences in dietary intake between SGA and NGA boys were found. In summary, girls born SGA had an unfavourable dietary intake compared with NGA girls. These differences persisted after controlling for potential confounders, thus supporting a fetal programming effect on dietary intake in girls born SGA at term. However, residual confounding by other factors operating early in childhood cannot be excluded.

Vitamin D fortification and seasonality of birth in type 1 diabetic cases: D-tect study.

Fortification of margarine with vitamin D was mandatory in Denmark during 1961-1985. The aim of the study was to assess whether gestational and early infancy exposure to margarine fortification was associated with seasonality of birth in Danish type 1 diabetes (T1D) patients. The risks of T1D in Danes born during various exposure periods around margarine fortification termination in 1985 were analyzed. As expected, the T1D hazards in males unexposed to margarine fortification and born in spring were higher than in males born in autumn: relevant hazard ratios (95% confidence intervals) in various exposure groups ranged from 1.74 (1.112/2.708) to 37.43 (1.804/776.558). There were no indications of seasonality of birth in males exposed to fortification, nor in both exposed and unexposed females. The study suggests that early life exposure to low-dose vitamin D from fortified food eliminates seasonality of birth in T1D male patients. Further studies are required to investigate the identified gender differences.

Local skin-fold thickness as a clinical predictor of depot size during basal rate infusion of insulin.

OBJECTIVE: To determine the influence of local adiposity on insulin depot size during CSII at basal rate. RESEARCH DESIGN AND METHODS: In 27 diabetic patients, a constant infusion of 125I-labeled Actrapid insulin was given, with U-40 insulin at a rate of 1.12 IU/h in 20 patients, and U-100 at a rate of 1 IU/h in 7 patients. After 16 h of infusion, the steady-state depot size was measured by external counting, and the local skin fold was measured with a Harpenden skin-fold caliper. RESULTS: U-40 insulin infusion resulted in a steady-state depot size of 5.1 U (2.1-10.9 U), and a corresponding skin-fold thickness of 17.8 mm (5-34 mm). A positive correlation was found between depot size and skin-fold thickness. A similar correlation was observed with U-100 insulin. CONCLUSIONS: During basal rate CSII, large variations in local skin-fold thickness create large variations in the steady-state depot size, which is partly predictable just by lifting the skin fold.

Normal insulin-stimulated endothelial function and impaired insulin-stimulated muscle glucose uptake in young adults with low birth weight.

Low birth weight has been linked to insulin resistance and cardiovascular disease. We hypothesized that insulin sensitivity of both muscle and vascular tissues were impaired in young men with low birth weight. Blood flow was measured by venous occlusion plethysmography during dose-response studies of acetylcholine and sodium nitroprusside in the forearm of fourteen 21-yr-old men with low birth weight and 16 controls of normal birth weight. Glucose uptake was measured during intraarterial insulin infusion. Dose-response studies were repeated during insulin infusion. The maximal blood flow during acetylcholine infusion was 14.1 +/- 2.7 and 14.4 +/- 2.1 [ml x (100 ml forearm)(-1) x min(-1)] in low and normal birth weight subjects, respectively. Insulin coinfusion increased acetylcholine-stimulated flow in both groups: 18.0 +/- 3.1 vs. 17.9 +/- 3.1 [ml x (100 ml forearm)(-1) x min(-1)], NS. Insulin infusion increased glucose uptake significantly in the normal birth weight group, compared with the low birth weight group: 0.40 +/- 0.09 to 1.00 +/- 0.16 vs. 0.44 +/- 0.09 to 0.59 +/- 0.1 [ micro mol glucose x (100 ml forearm)(-1) x min(-1)], P = 0.04. Young men with low birth weight have normal insulin-stimulated endothelial function and impaired insulin-stimulated forearm glucose uptake. Thus, endothelial dysfunction does not necessarily coexist with metabolic alterations in subjects with low birth weight.

Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)--evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins.

The incremental glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses (areas under curves; AUCs) were determined during a standard 180-min 75-g oral glucose tolerance test in a group of 12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) and 13 matched controls without family history of diabetes using highly sensitive and specific radioimmunoassay hormone assays. Data were analysed using multifactor analysis of variance (ANOVA) to identify and correct for possible covariates and to correct for multiple comparisons. Fasting plasma GLP-1 and GIP concentrations were similar in all groups. The twins with frank NIDDM had a decreased incremental GLP-1 response during oral glucose ingestion compared with controls without family history of diabetes (AUC +/- SEM: 0.55 +/- 0.14 vs 1.17 +/- 0.25 (mmol/l) x min, p < 0.05). The incremental GLP-1 secretion in the non-diabetic twins was not significantly different from neither their NIDDM co-twins nor the controls without family history of diabetes. The incremental GIP responses were similar in all study groups. Gender was identified as the major independent covariate for incremental glucose, insulin, GIP and GLP-1 responses, with higher values of all parameters in females. Waist-to-hip ratio and body mass index (BMI) were identified as independent but oppositely directed covariates for the incremental GLP-1 responses (waist-to-hip ratio: r = 0.43, p < 0.02; BMI: r = -0.34, p = 0.06). Incremental GLP-1 responses correlated with incremental insulin responses in the combined study population (N = 37; R = 0.42, p = 0.01). In conclusion, a decreased intestinal GLP-1 secretion may contribute to the abnormal insulin secretion during oral glucose ingestion in NIDDM twins. However, decreased secretion of gut incretin hormones (GLP-1 or GIP) does not explain all of the defects of pancreatic insulin secretion in NIDDM patients/twins or in non-diabetic individuals (identical twins) with a genetic predisposition to NIDDM.

Glucose-fatty acid cycle operates in humans at the levels of both whole body and skeletal muscle during low and high physiological plasma insulin concentrations.

Plasma non-esterified fatty acid concentrations were elevated acutely (Intralipid+heparin infusion) in 14 normal humans in order to study the effects of fatty acids on whole-body basal and insulin-stimulated glucose metabolism, and on activities of skeletal muscle key enzymes. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated (3 h, 40 mU.m-2.min-1) steady-state periods. Total peripheral glucose uptake was unaffected by Intralipid infusion in the basal state, whereas it decreased during Intralipid infusion in the hyperinsulinemic state (10.7 +/- 0.7 vs 8.7 +/- 0.8 mg.kg-1 fat-free mass.min-1, p < 0.02). Intralipid infusion decreased whole-body glucose oxidation in the basal state (1.3 +/- 0.2 vs 0.8 +/- 0.1 mg.kg-1 fat-free mass.min-1, p < 0.001) and during hyperinsulinemia (3.6 +/- 0.2 vs 1.7 +/- 0.2 mg.kg-1 fat-free mass.min-1 p < 0.001). Whole-body nonoxidative glucose uptake increased during Intralipid infusion in the basal state and was unaffected in the hyperinsulinemic state. The skeletal muscle pyruvate dehydrogenase activity ratio decreased in the basal state during Intralipid infusion (55 +/- 6 vs 43 +/- 5%, p < 0.05), whereas no statistical significant decrease in the pyruvate dehydrogenase activity ratio was observed during insulin infusion (57 +/- 8 vs 47 +/- 5%, NS). Insulin increased the activity of the active form of pyruvate dehydrogenase on the control day, but not during Intralipid infusion. Activities of phosphofructokinase and glycogen synthase were unaffected by Intralipid infusion. Plasma glucose concentrations were similar during Intralipid infusion and on the control day, whereas Intralipid infusion increased the muscle glucose content in the basal state (1.36 +/- 0.09 vs 1.77 +/- 0.12 mmol/kg dry wt, p < 0.05) and in the hyperinsulinemic state (1.23 +/- 0.09 vs 1.82 +/- 0.16 mmol/kg dry wt, p < 0.05). Insulin increased the muscle lactate content on the control day (6.50 +/- 0.95 vs 8.65 +/- 0.77 mmol/kg dry wt, p < 0.05), but not during Intralipid infusion. In conclusion, the glucose-fatty acid cycle operates in humans in vivo at the levels of both whole body and skeletal muscle during both low and high physiological insulin concentrations.

[Is low birth weight a risk factor for development of non-insulin-dependent diabetes mellitus?]. / Udgør lav fødselsvaegt en risikofaktor for udvikling af ikke-insulinkraevende diabetes mellitus?

Different lines of evidence indicate that low birth weight and insufficient intrauterine nutrition may represent significant risk factors for the development of late onset non-insulin dependent diabetes mellitus (NIDDM). The evidence includes epidemiological studies, animal studies and metabolic studies of non-diabetic subjects with low birth weight. Insufficient intrauterine nutrition may induce a variety of abnormalities of metabolism in different tissues including muscle, liver, pancreas and adipose tissue; which can all in turn be related to known defects of glucose metabolism involved in the development of hyperglycaemia in NIDDM. Future studies should address the important question as to which roles genetics versus intrauterine and postnatal factors play in the etiology of late onset NIDDM in the general population. This may have important implications for which initiatives that should be applied to prevent NIDDM.

[Low birth weight is associated with non-insulin-dependent diabetes mellitus in discordant monozygotic and dizygotic twins]. / Lav fødselsvaegt er associeret med ikke-insulinkraevende diabetes mellitus hos diskordante monozygote og dizygote tvillingepar.

Previous studies have demonstrated an association between low weight at birth and risk of later development of non-insulin dependent diabetes mellitus (NIDDM). It is unknown whether this association may be due to an impact of intrauterine malnutrition per se, or whether it may be due to a coincidence between the putative "NIDDM susceptibility genotype" and a genetically determined low weight at birth. We traced original midwife birthweight record determinations in a group of monozygotic (n = 14 pairs) and dizygotic (n = 14 pairs) twins who phenotypically appeared discordant for NIDDM at a mean age of 67 and 64 years respectively. Birthweights were lower in the NIDDM twins compared with both their identical and non-identical non-diabetic co-twins respectively (p < 0.02 both). Using a similar approach in twin pairs discordant for impaired glucose tolerance (IGT) per se, no significantly decreased birthweight was detected in the IGT twins compared with their non-diabetic co-twins. However, when a larger group of twins with different glucose tolerances were considered, birthweights were lower in twins with abnormal glucose tolerance including both NIDDM and IGT. Furthermore, the twins with the lowest birthweights among the two co-twins had the highest plasma glucose concentrations 120 min after the 75 g oral glucose load (n = 86 pairs, p = 0.02). The study supports the hypothesis that low birthweight and a non-genetically determined intrauterine component such af malnutrition may play a role for the development of NIDDM in twins.

[Injection site for quick-acting insulin. Significance for glycemic control in basal bolus insulin regimen]. / Injektionssted for hurtigtvirkende insulin. Betydning for glykoemisk kontrol ved basal-bolus insulinregimet.

The impact on glycaemic control of soluble insulin injected either intramuscularly into the thigh (IMT), subcutaneously into the abdominal wall (SCA) or subcutaneously into the thigh (SCT) was evaluated in 49 Type 1 diabetic outpatients following a randomised three-month intervention study. Insulin doses were adjusted based on patients' self-monitored blood glucose values and reported hypoglycaemic episodes. More patients in the SCA and IMT groups than in the SCT group had serum fructosamine values within normal limits following intervention. Blood glucose at 03.00 was lower in the SCT group than in the SCA and IMT groups, due to a higher number of low nocturnal blood glucose values (less than 4 mmol/l) in the SCT group. In conclusion, s.c. injection of soluble insulin into the abdominal wall or intramuscularly into the thigh is preferable compared to s.c. injection into the thigh in the basal bolus insulin delivery regimen. Soluble insulin injection s.c. into the thigh during daytime is a risk factor for nocturnal hypoglycaemia.

Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes.

Nutrition during early mammalian development permanently influences health of the adult, including increasing the risk of type 2 diabetes and coronary heart disease. However, the molecular mechanisms underlying such programming are poorly defined. Here we demonstrate that programmed changes in miRNA expression link early-life nutrition to long-term health. Specifically, we show that miR-483-3p is upregulated in adipose tissue from low-birth-weight adult humans and prediabetic adult rats exposed to suboptimal nutrition in early life. We demonstrate that manipulation of miR-483-3p levels in vitro substantially modulates the capacity of adipocytes to differentiate and store lipids. We show that some of these effects are mediated by translational repression of growth/differentiation factor-3, a target of miR-483-3p. We propose that increased miR-483-3p expression in vivo, programmed by early-life nutrition, limits storage of lipids in adipose tissue, causing lipotoxicity and insulin resistance and thus increasing susceptibility to metabolic disease.

Sustained postprandial decrease in plasma levels of LDL cholesterol in patients with type-2 diabetes mellitus.

OBJECTIVE: Low density lipoprotein cholesterol (LDL-C) is an independent and modifiable risk factor for development of cardiovascular disease (CVD). Postprandial lipid metabolism has been linked to CVD, but little is known about the postprandial LDL-C profile in patients with type-2 diabetes (T2DM). We aimed to study the postprandial levels of LDL-C in T2DM patients. MATERIAL AND METHODS: After an overnight fast, 74 T2DM patients, mean age approximately 60 years, were served a standard fat-rich meal of 3515 kJ containing 54% fat, 13 % protein and 33 % carbohydrates. Only drinking water was allowed postprandially. Blood samples were drawn at times 0 (fasting), 1.5, 3.0, 4.5 and 6.0 h (postprandial). In all samples, LDL-C was measured with modified beta quantification (separation by ultracentrifugation followed by measurement of infranate high density lipoprotein cholesterol (HLD-C) using a homogeneous assay). RESULTS: At all postprandial times, levels of LDL-C showed highly significant (p < 0.005) decreases compared to time 0 (mean [95% CI] maximum change in LDL-C levels at 3.0 h: -0.16 mmol/L [-0.12; -0.20]; p < 0.001). Independently of fasting LDL-C levels and ongoing statin therapy, LDL-C decreased significantly more in female compared to male patients postprandially (mean [95% CI] maximum unadjusted change versus time 0 in LDL-C for men [n=56] at 3.0 h: -0.14 mmol/L [-0.19; -0.10], p < 0.001; for women [n=18] at 4.5 h: -0.26 mmol/L [-0.35; -0.18], p < 0.001; -0.14 mmol/L [-0.24; -0.05], p = 0.005 between genders for the mean [95% CI] fasting adjusted difference at 4.5 h in the change versus time 0 in LDL-C; gender by time interaction: p = 0.007 (repeated measures mixed model)). CONCLUSIONS: In T2DM patients served a fat-rich meal, levels of LDL-C decreased significantly more in women compared to men postprandially, irrespective of fasting levels or ongoing statin therapy. This might have implications in the atherosclerotic process and on any difference in the risk of CVD between genders.

Consequences of low birthweight on urinary excretion of DNA markers of oxidative stress in young men.

OBJECTIVE: Low birthweight (LBW) has been associated with an increased risk of development of type 2 diabetes in adult life. Both type 1 and type 2 diabetes mellitus are characterized by increased oxidative stress. The purpose of this study was to investigate whether young healthy adults born with LBW showed differences in oxidative stress under normal conditions and during the added challenge of a physiological Intralipid infusion. MATERIAL AND METHODS: Urinary excretion of DNA markers of oxidative stress were analyzed by LC-MS/MS in 19 men (aged 19 years) with LBW and in 19 age matched, normal birthweight (NBW) controls pre- and post a 3-fold increase of plasma free fatty acids. RESULTS: Mean excretion rates of 8-oxo-guanine (8oxoGua), 8-oxo-guanosine (8oxoGuo), 8-oxo-2'deoxyguanosine (8oxodG), and 1,N6-ethenodeoxyadenosine (epsilon dA) did not statistically differ between subjects with LBW and NBW (66.9 versus 73.9 nmol/15 h, 17.8 versus 18.5 nmol/15 h, 11.9 versus 14.4 nmol/15 h and 44.0 versus 43.2 pmol/15 h, respectively). Furthermore, Intralipid infusion did not affect excretion of DNA adducts in LBW or NBW subjects. Statistically significant correlations were found between body mass index and urinary excretion of 8oxoGua (r = 0.64, p = 0.003) and 8oxoGuo (r = 0.64, p = 0.003) in the LBW group only. CONCLUSIONS: These findings suggest that oxidative stress may be a consequence of diabetes and is not, or at least only partly, involved in the early pathogenesis of type 2 diabetes.