The regenerative process in the pancreas is of particular interest, since insulin-producing beta cells are lost in diabetes. Differentiation of new beta cells from pancreatic non-endocrine cells has been reported in vivo and in vitro, a finding that implies the existence of pancreatic stem/progenitor cells. However, while tissue-specific stem cells are well documented in skin, intestine and testis, pancreatic stem cells have been elusive. We hypothesised that pancreatic stem/progenitor cells within the non-endocrine fraction could be a source of new islets in vitro.
To test if there were such cells within the pancreas, we generated pancreatic cell aggregates from tissue remaining after islet isolation from mouse insulin promoter 1–green fluorescent protein (MIP-GFP) mice. To eliminate any contamination of insulin-positive cells, we deleted all GFP-positive aggregates using COPAS Select and cultured with Matrigel. Immunohistochemistry, quantitative real-time PCR and single-cell nested RT-PCR were performed to confirm formation of insulin-producing cells.
The GFP-negative cells were expanded as monolayers and then differentiated into three-dimensional cystic structures. After 1 week of culture, GFP-positive cells were found as clusters or single cells. By quantitative real-time PCR, no insulin mRNA was detected immediately after COPAS sorting, but after differentiation insulin mRNA of the whole preparation was 1.91±0.31% that of purified MIP-GFP beta cells. All GFP-positive cells expressed insulin 1; most expressed insulin 2, pancreas duodenum homeobox-1 and cytokeratin 19 by single cell nested RT-PCR.
Our data support the concept that within the exocrine (acinar and ductal) pancreas of the adult mouse there are cells that can give rise to insulin-positive cells in vitro.
Beta cell; Duct; Neogenesis; Pancreas
Islet transplantation is a promising treatment for type 1 diabetes but is hampered by a shortage of donor human tissue and early failure. Research on islet-cell transplantation includes finding new sources of cells and immunoisolation to protect from immune assault and tumorigenic potential. Small islet-cell aggregates were studied to determine if their survival and function were superior to intact islets within microcapsules because of reduced oxygen transport limitation and inflammatory mediators.
Islet-cell aggregates were generated by dispersing rat islets into single cells and allowing them to re-aggregate in culture. Rat islets and islet-cell aggregates were encapsulated in barium alginate capsules and studied when cultured in low (0.5% or 2%) or normal (20%) oxygen, or transplanted into mice.
Encapsulated islet-cell aggregates were able to survive and function better than intact islets in terms of oxygen-consumption rate, nuclei counts, insulin-to-DNA ratio, and glucose-stimulated insulin secretion. They also had reduced expression of pro-inflammatory genes. Islet-cell aggregates showed reduced tissue necrosis in an immunodeficient transplant model and a much greater proportion of diabetic xenogeneic transplant recipients receiving islet-cell aggregates (tissue volume of only 85 islet equivalents) had reversal of hyperglycaemia than recipients receiving intact islets.
These aggregates were superior to intact islets in terms of survival and function in low-oxygen culture and during transplantation and are likely to provide more efficient utilisation of islet tissue, a finding of importance for the future of cell therapy for diabetes.
Little is known about the performance of surrogates in assessing changes in insulin sensitivity over time. This report compared updated HOMA of insulin sensitivity (HOMA2-%S) and the Matsuda index from OGTTs with minimal model-based estimates of insulin sensitivity (SI) from frequently sampled IVGTTs (FSIGTs) in longitudinal settings and cross-sectional settings.
Two longitudinal studies were used: one a natural observational study in which 338 individuals were followed for a median of 4 years; one a clinical treatment study in which 97 individuals received pioglitazone treatment and were followed for 1 year. Pairs of OGTTs and FSIGTs were performed at baseline and follow-up. Correlations were computed. Impact of measurement uncertainty was investigated through simulation studies.
Correlations between HOMA2-%S and SI from baseline or follow-up data were in the range reported previously (0.61-0.69). By contrast, correlations for changes over time were only 0.35-0.39. The corresponding correlations between the Matsuda index and SI were 0.66-0.72 for cross-sectional data and 0.40-0.48 for longitudinal change. Correlations for changes were significantly lower than the cross-sectional correlations in both studies (p<0.03). Simulation results demonstrated that the reduced correlations for change were not explained by error propagation, supporting a real limitation of surrogates to fully capture longitudinal changes in insulin sensitivity.
HOMA and Matsuda indices derived from cross-sectional data should be used cautiously in assessing longitudinal changes in insulin sensitivity.
Homeostasis models; Insulin sensitivity surrogates; Intravenous glucose tolerance test; Longitudinal change; Oral glucose tolerance test
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with anti-apoptotic effects on the pancreatic beta cell. The aim of this study was to generate transgenic mice with fluorescently labelled GIP-secreting K cells and to use these to investigate pathways by which K cells detect nutrients.
Transgenic mice were generated in which the GIP promoter drives the expression of the yellow fluorescent protein Venus. Fluorescent cells were purified by flow cytometry and analysed by quantitative RT-PCR. GIP secretion was assayed in primary cultures of small intestine.
Expression of Venus in transgenic mice was restricted to K cells, as assessed by immunofluorescence and measurements of the Gip mRNA and GIP protein contents of purified cells. K cells expressed high levels of mRNA for Kir6.2 (also known as Kcnj11), Sur1 (also known as Abcc8), 1 Sglt1 (also known as Slc5a1), and of the G-protein-coupled lipid receptors Gpr40 (also known as Ffar1), Gpr119 and Gpr120. In primary cultures, GIP release was stimulated by glucose, glutamine and linoleic acid, and potentiated by forskolin plus 3-isobutyl-1-methylxanthine (IBMX), but was unaffected by the artificial sweetener sucralose. Secretion was half-maximal at 0.6 mmol/l glucose and partially mimicked by α-methylglucopyranoside, suggesting the involvement of SGLT1. Tolbutamide triggered secretion under basal conditions, whereas diazoxide suppressed responses in forskolin/IBMX.
These transgenic mouse and primary culture techniques provide novel opportunities to interrogate the mechanisms of GIP secretion. Glucose-triggered GIP secretion was SGLT1-dependent and modulated by KATP channel activity but not determined by sweet taste receptors. Synergistic stimulation by elevated cAMP and glucose suggests that targeting appropriate G-protein-coupled receptors may provide opportunities to modulate GIP release in vivo.
cAMP; GIP; Incretin; K cells; SGLT1
AMP-activated protein kinase (AMPK) is an evolutionarily-conserved enzyme and a target of antihyperglycemic agents including metformin. However, the precise role(s) of the enzyme in controlling insulin secretion remains uncertain.
The catalytic α1 and α2 subunits of AMPK were ablated selectively in pancreatic beta cells and hypothalamic neurons by breeding AMPKα1 null mice, bearing flox’d AMPKα2 alleles, with animals expressing Cre recombinase under the rat insulin promoter. The latter promoter was used to express constitutively-activated AMPK selectively in beta cells in transgenic mice. Food intake, body weight and urinary catecholamines were measured using metabolic cages. Glucose and insulin tolerance were determined after intraperitoneal injection. Beta cell mass and morphology were analysed by optical projection tomography and confocal immunofluorescence microscopy, respectively. Granule docking, insulin secretion, membrane potential, and intracellular free Ca2+ were measured with standard techniques.
Trigenic βAMPKdKO mice, lacking both AMPK α subunits in the beta cell, displayed normal body weight and increased insulin sensitivity, but were profoundly insulin deficient. Secreted catecholamine levels were unchanged. Total beta cell mass was unaltered whilst mean islet and beta cell volume were reduced. AMPK-deficient beta cells displayed normal glucose-induced changes in membrane potential and intracellular free Ca2+ whilst granule docking and insulin secretion were enhanced. Conversely, βAMPK transgenic mice were glucose-intolerant and displayed defective insulin secretion.
Inhibition of AMPK activity within the beta cell is necessary, but not sufficient, for the stimulation of insulin secretion by glucose. AMPK activation in extrapancreatic RIP.Cre-expressing cells might also influence insulin secretion in vivo
Recent studies suggest that wingless-type MMTV integration site family, member 10B (WNT10B) may play a role in the negative regulation of adipocyte differentiation in vitro and in vivo. In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene.
Subjects and methods
We studied 96 subjects with severe obesity of early onset (less than 10 years of age) from the UK Genetics of Obesity Study and 115 obese Italian subjects of European origin.
One proband with early-onset obesity was found to be heterozygous for a C256Y mutation, which abrogated the ability of WNT10B to activate canonical WNT signalling and block adipogenesis and was not found in 600 control alleles. All relatives of the proband who carried this allele were either overweight or obese. Three other rare missense variants were found in obese probands, but these did not clearly cosegregate with obesity in family studies and one (P301S), which was found in three unrelated subjects with early-onset obesity, had normal functional properties.
These mutations represent the first naturally occurring missense variants of WNT10B. While the pedigree analysis in the case of C256Y WNT10B does not provide definitive proof of a causal link of this variant with obesity, the finding of a non-functioning WNT10B allele in a human family affected by obesity should encourage further study of this gene in other obese populations.
Adipocyte; Adipogenesis; Human; Obesity; WNT
Wingless and iNT-1 (WNT) pathway members are critical for pancreatic development and exocrine tissue formation. Recently, much attention has focused on delineating the roles of β-catenin in pancreatic organogenesis. However, little is known about the involvement of β-catenin in the endocrine or exocrine function of the mature pancreas. We report for the first time the impact of β-catenin deletion in the pancreatic beta cells.
We targeted the deletion of the β-catenin gene in pancreatic beta cells by crossing a floxed β-catenin mouse strain with a RIP-Cre mouse strain.
Surprisingly, the majority of the mutant mice died shortly after birth and had deregulated glucose and insulin levels. The newborn mutant pancreases demonstrated increased insulin content, reflecting a defect in insulin release confirmed in vitro. Moreover, there was a reduction in total endocrine tissue at birth, while cellularity in islets was greater, suggesting that lack of β-catenin affects beta cell size. Some newborns survived β-catenin deletion and showed a milder phenotype during adulthood.
The deletion of β-catenin in the maturing beta cells negatively impacts on islet morphology and function. This work reveals that lack of β-catenin in early life is related to severe deregulation of glucose homeostasis.
Beta-catenin; Beta cell; Insulin secretion; Pancreas; WNT
The benefits of moderate alcohol consumption for type 2 diabetes have been postulated to involve a mechanism of improved insulin sensitivity. Fetuin-A, which is known to inhibit insulin signalling, has emerged as a biomarker for diabetes risk. Alcohol consumption may influence circulating fetuin-A concentrations and subsequently diabetes risk by altering the insulin signal. We therefore hypothesised that moderate alcohol consumption would be associated with lower fetuin-A concentration and that fetuin-A would partly explain the association between alcohol consumption and incident type 2 diabetes.
Among diabetes-free female participants in the Nurses’ Health Study (n=1331), multiple linear regression was conducted to assess the association between alcohol consumption and plasma fetuin-A. Least-squares means (lsmeans) of fetuin-A were estimated in categories of alcohol consumption (0, 0.1-4.9, 5-14.9 and ≥15 g/day). The proportion of alcohol consumption and diabetes association explained by baseline fetuin-A was assessed in 470 matched incident diabetes case–control pairs with follow-up 2000-2006.
Higher alcohol consumption was associated with lower plasma fetuin-A (p for trend=0.009): lsmean±SE 476.5±5.9 μg/ml for abstainers, 468.9±5.2 μg/ml for 0.1-4.9 g/day consumers, 455.9±7.0 μg/ml for 5.0-14.9 g/day consumers, and 450.0±9.4 μg/ml for ≥15.0 g/day consumers. Fetuin-A and fasting insulin explained 18.4% and 54.8%, respectively, of the inverse association between alcohol consumption and diabetes after multiple adjustment (both p for contribution <0.04).
Moderate alcohol consumption is associated with lower plasma fetuin-A in diabetes-free women. Fetuin-A and insulin explain a significant proportion of the association between alcohol consumption and incident type 2 diabetes. Further studies are needed to examine potential biological mechanisms underlying this association.
Alcohol; Fetuin-A; Insulin sensitivity; Type 2 diabetes
White cell count has been shown to predict incident type 2 diabetes, but differential white cell count has received scant attention. We examined the risk of developing diabetes associated with differential white cell count and neutrophil:lymphocyte ratio and the effect of insulin sensitivity and subclinical inflammation on white cell associations.
Incident diabetes was ascertained in 866 participants aged 40–69 years in the Insulin Resistance Atherosclerosis Study after a 5 year follow-up period. The insulin sensitivity index (SI) was measured by the frequently sampled IVGTT.
C-reactive protein was directly and independently associated with neutrophil (p<0.001) and monocyte counts (p<0.01) and neutrophil:lymphocyte ratio (p<0.001), whereas SI was inversely and independently related to lymphocyte count (p<0.05). There were 138 (15.9%) incident cases of diabetes. Demographically adjusted ORs for incident diabetes, comparing the top and bottom tertiles of white cell (1.80 [95% CI 1.10, 2.92]), neutrophil (1.67 [1.04, 2.71]) and lymphocyte counts (2.30 [1.41, 3.76]), were statistically significant. No association was demonstrated for monocyte count (1.18 [0.73, 1.90]) or neutrophil:lymphocyte ratio (0.89 [0.55, 1.45]). White cell and neutrophil associations were no longer significant after further adjusting for family history of diabetes, fasting glucose and smoking, but the OR comparing the top and bottom tertiles of lymphocyte count remained significant (1.92 [1.12, 3.29]). This last relationship was better explained by SI rather than C-reactive protein.
A lymphocyte association with incident diabetes, which was the strongest association among the major white cell types, was partially explained by insulin sensitivity rather than subclinical inflammation.
Clinical science; Epidemiology; Human; Insulin sensitivity and resistance; Pathogenic mechanisms; Prediction and prevention of type 2 diabetes
The relations between smoking and glycaemic parameters are not well explored. We compare HbA1c, fasting plasma glucose (FPG) and 2-hour plasma glucose (2H-PG) in current-, ex- and never-smokers.
This meta-analysis used individual data from 16 886 men and 18 539 women without known diabetes, in 12 DETECT-2 consortium studies and in the French D.E.S.I.R. and TELECOM studies. Means of the three glycaemic parameters in current-, ex- and never-smokers were modelled by linear regression, with study as a random factor. The I2 statistic evaluated heterogeneity among studies.
HbA1c was 0.10 (95%CI:0.08,0.12) % [1.1 (0.9,1.3) mmol/mol] higher in current-smokers and 0.03 (0.01,0.05) % [0.3 (0.1,0.5) mmol/l] higher in ex-smokers, compared with never-smokers. For FPG, there was no significant difference between current- and never-smokers: −0.004 (−0.03,0.02) mmol/l but FPG was higher in ex-smokers: 0.12 (0.09,0.14) mmol/l. In comparison to never-smokers, 2H-PG was lower: −0.44 (−0.52,−0.37) mmol/l in current-smokers, with no difference for ex-smokers: 0.02 (−0.06,0.09) mmol/l. There was a large and unexplained heterogeneity among studies, with I2 always higher than 50%: after stratification by sex and adjustment for age and BMI, I2 changed little. In this study population, current-smokers had a prevalence of diabetes as screened by HbA1c, 1.30% higher and that screened by 2H-PG, 0.52% lower than in comparison to never-smokers.
Current-smokers had a higher HbA1c and a lower 2H-PG than never-smokers, across this heterogeneous group of studies; this will effect the chances of smokers being diagnosed with diabetes.
HbA1c; FPG; 2H-PG; smoking
Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR.
Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints.
NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood–retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes.
These results indicate that NRF2 is an important protective mechanism regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.
Diabetic retinopathy; Inflammation; Müller glial cells; Neuronal dysfunction; NF-E2-related factor-2; Reactive oxygen species; Transcription factor; Vascular permeability
Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)–oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1–oestrogen during beta cell failure under glucolipotoxic conditions.
Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1–oestrogen, respectively. Subsequently, the effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1–oestrogen, transcription analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed.
In contrast to GLP-1, GLP-1–oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed elevated expression of Pomc and Leprb. In livers from GLP-1–oestrogen-treated mice, expression of lipogenic genes was attenuated and hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1–oestrogen altered the mRNA expression to a pattern that was similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather indirect protection of pancreatic beta cells.
GLP-1–oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic capacity of GLP-1 alone.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3478-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Beta cells; GLP-1; Liver fat; NZO; Oestrogen; Pomc
Lower birthweight (a marker of fetal undernutrition) is associated with higher risks of type 2 diabetes and cardiovascular disease (CVD) and could explain ethnic differences in these diseases. We examined associations between birthweight and risk markers for diabetes and CVD in UK-resident white European, South Asian and black African-Caribbean children.
In a cross-sectional study of risk markers for diabetes and CVD in 9- to 10-year-old children of different ethnic origins, birthweight was obtained from health records and/or parental recall. Associations between birthweight and risk markers were estimated using multilevel linear regression to account for clustering in children from the same school.
Key data were available for 3,744 (66%) singleton study participants. In analyses adjusted for age, sex and ethnicity, birthweight was inversely associated with serum urate and positively associated with systolic BP. After additional height adjustment, lower birthweight (per 100 g) was associated with higher serum urate (0.52%; 95% CI 0.38, 0.66), fasting serum insulin (0.41%; 95% CI 0.08, 0.74), HbA1c (0.04%; 95% CI 0.00, 0.08), plasma glucose (0.06%; 95% CI 0.02, 0.10) and serum triacylglycerol (0.30%; 95% CI 0.09, 0.51) but not with BP or blood cholesterol. Birthweight was lower among children of South Asian (231 g lower; 95% CI 183, 280) and black African-Caribbean origin (81 g lower; 95% CI 30, 132). However, adjustment for birthweight had no effect on ethnic differences in risk markers.
Birthweight was inversely associated with urate and with insulin and glycaemia after adjustment for current height. Lower birthweight does not appear to explain emerging ethnic difference in risk markers for diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3474-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Birthweight; Cardiovascular disease; Childhood; Ethnicity; Type 2 diabetes
Pancreatic beta cells play a central role in the control of glucose homeostasis by secreting insulin to stimulate glucose uptake by peripheral tissues. Understanding the molecular mechanisms that control beta cell function and plasticity has critical implications for the pathophysiology and therapy of major forms of diabetes. Selective gene inactivation in pancreatic beta cells, using the Cre-lox system, is a powerful approach to assess the role of particular genes in beta cells and their impact on whole body glucose homeostasis. Several Cre recombinase (Cre) deleter mice have been established to allow inactivation of genes in beta cells, but many show non-specific recombination in other cell types, often in the brain.
We describe the generation of Ins1Cre and Ins1CreERT2 mice in which the Cre or Cre-oestrogen receptor fusion protein (CreERT2) recombinases have been introduced at the initiation codon of the Ins1 gene.
We show that Ins1Cre mice induce efficient and selective recombination of floxed genes in beta cells from the time of birth, with no recombination in the central nervous system. These mice have normal body weight and glucose homeostasis. Furthermore, we show that tamoxifen treatment of adult Ins1CreERT2 mice crossed with Rosa26-tdTomato mice induces efficient recombination in beta cells.
These two strains of deleter mice are useful new resources to investigate the molecular physiology of pancreatic beta cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3468-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Beta cells; Cre recombinase; Glucose homeostasis; Hypothalamus; Insulin; Pancreatic islets; Transgenic mice
We tested the hypothesis that age younger than 65 years at type 2 diabetes diagnosis is associated with worse subsequent glycaemic control.
A cross-sectional analysis of data from participants in the 2005–2010 National Health and Nutrition Examination Survey was performed. For adults with self-reported diabetes, we dichotomised age at diabetes diagnosis as younger (<65 years) vs older (≥65 years). The primary outcome of interest was HbA1c >9.0% (75 mmol/mol). Secondary outcomes were HbA1c >8.0% (64 mmol/mol) and >7.0% (53 mmol/mol). We used multivariable logistic regression for analysis.
Among 1,438 adults with diabetes, a higher proportion of those <65 years at diagnosis compared with those ≥65 at diagnosis had an HbA1c >9.0% (14.4% vs 2.5%, p<0.001). After adjustment for sex, race/ethnicity, education, income, insurance, usual source of care, hyperglycaemia medication, duration of diabetes, family history, BMI and waist circumference, age <65 years at diagnosis remained significantly associated with greater odds of HbA1c > 9.0% (OR 3.22, 95% CI 1.54, 6.72), HbA1c > 8.0% (OR 2.72, 95% CI 1.43, 5.16) and HbA1c >7.0% (OR 1.92, 95% CI 1.18, 3.11). The younger group reported fewer comorbidities, but were less likely to report good health (OR 0.54, 95% CI 0.36, 0.83).
Younger age at type 2 diabetes diagnosis is significantly associated with worse subsequent glycaemic control. Because patients who are younger at diagnosis have fewer competing comorbidities and complications, safe, aggressive, individualised treatment could benefit this higher-risk group.
Ageing; Diabetes mellitus; Epidemiology; Prevention and control
Glycaemic control; HbA1c; Glycated haemoglobin; Epidemiology; Diabetes in the elderly; National survey; Survival bias
The aim of the study was to compare longitudinal changes in insulin sensitivity (SI) and beta cell function between women with and without a history of gestational diabetes mellitus (GDM).
The prospective follow-up cohort included 235 parous non-diabetic Mexican-American women, 93 with and 142 without a history of GDM. The participants underwent dual-energy x-ray absorptiometry, OGTTs and IVGTTs at baseline and at a median of 4.1 years follow-up. The baseline values and rates of change of metabolic measures were compared between groups.
At baseline, women with prior GDM (mean age 36.3 years) had similar values of SI but higher percentages of body fat and trunk fat (p≤0.02), a lower acute insulin response and poorer beta cell compensation (disposition index [DI]) (p<0.0001) than women without GDM (mean age 37.9 years). During the follow-up, women with GDM had a faster decline in SI (p=0.02) and DI (p=0.02) than their counterparts without GDM, with no significant differences in changes of weight or fat (p>0.50). Adjustment for baseline age, adiposity, calorie intake, physical activity, age at first pregnancy, additional pregnancies and changes in adiposity during follow-up increased the between-group differences in the rates of change of SI and DI (p≤0.003).
Mexican-American women with recent GDM had a faster deterioration in insulin sensitivity and beta cell compensation than their parous counterparts without GDM. The differences were not explained by differences in adiposity, suggesting more deleterious effects of existing fat and/or reduced beta cell robustness in women with GDM.
Beta cell function; Gestational diabetes mellitus; Longitudinal change; Insulin sensitivity