ER stress in rodent islets of Langerhans is concomitant with obesity and β-cell compensation but not with β-cell dysfunction and diabetes

Objective:

The objective of this study was to determine whether ER stress correlates with β-cell dysfunction in obesity-associated diabetes.

Methods:

Quantitative RT-PCR and western blot analysis were used to investigate changes in the expression of markers of ER stress, the unfolded protein response (UPR) and β-cell function in islets isolated from (1) non-diabetic Zucker obese (ZO) and obese female Zucker diabetic fatty (fZDF) rats compared with their lean littermates and from (2) high-fat-diet-fed fZDF rats (HF-fZDF), to induce diabetes, compared with age-matched non-diabetic obese fZDF rats.

Results:

Markers of an adaptive ER stress/UPR and β-cell function are elevated in islets isolated from ZO and fZDF rats compared with their lean littermates. In islets isolated from HF-fZDF rats, there was no significant change in the expression of markers of ER stress compared with age matched, obese, non-diabetic fZDF rats.

Conclusions:

These results provide evidence that obesity-induced activation of the UPR is an adaptive response for increasing the ER folding capacity to meet the increased demand for insulin. As ER stress is not exacerbated in high-fat-diet-induced diabetes, we suggest that failure of the islet to mount an effective adaptive UPR in response to an additional increase in insulin demand, rather than chronic ER stress, may ultimately lead to β-cell failure and hence diabetes.     

Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance

Aims/hypothesis  

We examined in skeletal muscle (1) whether fatty acid transport protein (FATP) 1 channels long-chain fatty acid (LCFA) to specific metabolic fates in rats; and (2) whether FATP1-mediated increases in LCFA uptake exacerbate the development of diet-induced insulin resistance in mice. We also examined whether FATP1 is altered in insulin-resistant obese Zucker rats.     

Analysis of pancreatic volume in acute‐onset,slowly‐progressive and fulminant type 1 diabetes in a Japanese population

Aims/Introduction

A decrease in the size of the pancreas is observed in islet autoantibody‐positive non‐diabetic donors and acute‐onset type 1 diabetes irrespective of the diabetes duration. Little is known, however, about the relationship between the size of the pancreas and type 1 diabetes subtypes, including fulminant type 1 diabetes.

Materials and Methods

We examined the pancreatic volume (PV) in 44 adult patients with type 1 diabetes (16 acute‐onset type 1 diabetes, 18 slowly progressive type 1 diabetes and 10 fulminant type 1 diabetes) and 39 age‐ and body mass index‐matched non‐diabetic controls. PV was measured by computed tomography. The ability to secrete insulin was assessed by stimulated C‐peptide after intravenous glucagon administration.

Results

PV was significantly correlated with bodyweight in both control participants and type 1 diabetes patients. The PV index (PVI; PV/bodyweight) was decreased by 39% in type 1 diabetes compared with that in controls. PVI was significantly decreased in acute‐onset type 1 diabetes patients and slowly progressive type 1 diabetes patients (both P < 0.0001), but not in fulminant type 1 diabetes patients (P = 0.10), compared with control participants. In cases patients with recent‐onset type 1 diabetes (0–7 days post‐diagnosis), PVI was significantly decreased in acute‐onset type 1 diabetes patients (n = 8, P = 0.0005), but not in fulminant type 1 diabetes patients (n = 7, P = 0.44), compared with controls. PVI showed no correlations with the diabetes duration, C‐peptide levels, glycated hemoglobin, glutamic acid decarboxylase autoantibody levels, serum amylase or daily total insulin dose in type 1 diabetes subtypes.

Conclusions

The present results show that patients with acute‐onset type 1 diabetes and slowly progressive type 1 diabetes have small pancreases irrespective of the diabetes duration or C‐peptide levels. In contrast to earlier findings on acute‐onset type 1 diabetes, we found no reduction of PVI at the onset of fulminant type 1 diabetes.     

Ovarian morphology and prevalence of polycystic ovary syndrome in Japanese women with type 1 diabetes mellitus

Aims/Introduction

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder including polycystic ovary morphology (PCOM), ovulatory dysfunction and hyperandrogenism. PCOS is frequently associated with type 2 diabetes mellitus; however, it is unknown whether PCOM and PCOS are prevalent in Japanese patients with type 1 diabetes mellitus. The purpose of our study was to determine the frequency of PCOM and PCOS in women with type 1 diabetes mellitus.

Materials and Methods

We evaluated clinical, hormonal and ovarian ultrasound data from 21 type 1 diabetes mellitus patients whose average glycated hemoglobin levels were 7.9 ± 1.5%.

Results

Ultrasound identified PCOM in 11 patients (52.4%) and these patients also had higher levels of the androgen dehydroepiandrosterone sulfate (DHEA‐S) than those without PCOM (P < 0.05). Of the patients with PCOM, five presented menstrual irregularities (45.5%) and three met the Japanese criteria for PCOS (27.2%); whereas all patients without PCOM had a normal menstrual cycle (P < 0.05).

Conclusions

Japanese premenopausal women with type 1 diabetes mellitus had a high frequency of PCOM as well as PCOS. This is the first research of this area carried out in an Asian population.     

Apolipoprotein M can discriminate HNF1A‐MODY from Type 1 diabetes

Aims

Missed diagnosis of maturity‐onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)‐MODY because of its reduced expression in Hnf1a^–/– mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A‐MODY using a highly specific and sensitive ELISA.

Methods

ApoM concentration was measured in subjects with HNF1A‐MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated.

Results

Mean (standard deviation) serum apoM concentration (μmol/l) was significantly lower for subjects with HNF1A‐MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10^–18) and control subjects [1.34 (0.22), P = 7.2 × 10^–19). There was no significant difference in apoM concentration between subjects with HNF1A‐MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C‐statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A‐MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A‐MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A‐MODY from either Type 1 diabetes (C‐statistic = 0.79) or Type 2 diabetes (C‐statistic = 0.68).

Conclusions

We confirm an earlier report that serum apoM levels are lower in HNF1A‐MODY than in controls. Serum apoM provides good discrimination between HNF1A‐MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics.     

Systematic review and meta‐analysis of psychological interventions in people with diabetes and elevated diabetes‐distress

Aims

The clinical relevance of diabetes‐distress is increasingly recognized, but little is known about the efficacy of interventions specifically targeted to treat elevated diabetes‐distress. Therefore, this systematic review sought to determine the efficacy of psychological interventions aimed at treating elevated diabetes‐distress in people with Type 1 or Type 2 diabetes.

Methods

We systematically searched literature from five databases. Randomized controlled trials (RCTs) with an English abstract, describing the results of a psychological intervention in adults with diabetes were included. Articles were eligible for inclusion if the primary outcome was diabetes‐distress measured by the Problem Areas in Diabetes Scale (PAID‐5/PAID‐20) or the Diabetes Distress Scale (DDS‐17). Only mean group diabetes‐distress values above cut‐off at baseline or the results of a subgroup above cut‐off (PAID‐5 ≥ 8, PAID‐20 ≥ 40 or DDS‐17 ≥ 3) were included.

Results

The search yielded 8907 articles. After removing 2800 duplicates, 6107 articles remained. Titles and abstracts were screened, leaving 394 potential articles of interest, nine of which were RCTs. In a random‐effects meta‐analysis, the pooled effect size for diabetes‐distress was 0.48 (Cohen's d), Z = 3.91, P < 0.0001. Statistical heterogeneity was I² = 46.67% (confidence intervals 45.06% to 48.28%). Diabetes‐tailored psychological interventions reduced HbA_1c (Cohen's d = 0.57), whereas mindfulness‐based interventions did not (Cohen's d = 0.11).

Conclusions

This systematic review shows that specifically diabetes‐tailored psychological interventions are effective in reducing elevated diabetes‐distress and HbA_1c. More rigorous studies are warranted to establish the full potential of these interventions. PROSPERO database registration ID: CRD42017075290.     

Increasing achievement of the target goals for glycemic,blood pressure and lipid control for adults with diagnosed diabetes in Korea

Aims/Introduction

We investigated the prevalence, treatment and control of diagnosed diabetes in Korean adults from 1998 to 2010.

Materials and Methods

The Korean Ministry of Health and Welfare carried out the Korean National Health and Nutrition Examination Survey (KNHANES) in the years 1998 (I), 2001 (II), 2005 (III), 2007–2009 (IV) and 2010 (V). We estimated the prevalence of diagnosed diabetes in Korean adults and the proportions of well‐controlled diabetes, as defined by having glycosylated hemoglobin <7.0%, blood pressure <130/80 mmHg and low density lipoprotein (LDL) cholesterol <100 mg/dL according to the American Diabetes Association.

Results

The prevalence of diagnosed diabetes increased significantly from 3.2% in 1998 to 6.4% in 2010 (P < 0.0001). The prevalence of adults with diagnosed diabetes achieving blood pressure and LDL cholesterol target levels increased from 23.8% to 54.2% (P < 0.0001), and 25.7% to 47.7% (P<0.0001), respectively. However, the percentage of patients achieving glycemic goals did not increase significantly from 42.5% to 49.1% (P = 0.3034). Furthermore, there were significant increases in the proportions of individuals achieving all three target levels, from 2.7% in 2005 to 8.7% in 2010 (P < 0.0001).

Conclusions

The prevalence of diagnosed diabetes in Korea increased significantly from 1998 to 2010. The percentages of those achieving all recommendations of the American Diabetes Association have increased, but are still not satisfactory.     

Research on the relationships between pancreatic cancer and hyperglycemia in Chinese populations

Aims/Introduction

Pancreatic cancer (PC) is related to diabetes. Long‐standing diabetes should be a prerequisite, whereas new‐onset hyperglycemia might be a result of PC. However, the association between diabetes and PC is still in dispute.

Materials and Methods

We investigated the relationship between glucose metabolism and other factors by retrospectively analyzing the clinical data of 331 PC patients. Any histopathological type was eligible. The patients were divided into three groups: group A, normal glucose metabolism; group B, hyperglycemia duration≤6 months; and group C, diabetes duration >24 months.

Results

The prevalence of hyperglycemia was 59.5%. Most patients were diagnosed with diabetes mellitus either concomitantly with cancer (39.0%) or within 6 months before cancer diagnosis (6.9%). There were more females in group C than group A (P = 0.005) and B (P = 0.018). Patients in group A were younger (A vs B, P < 0.001; A vs C, P = 0.032) and thinner (A vs B, P = 0.013; A vs C, P = 0.027). In group C, more individuals shared a family history of diabetes (A vs C, P = 0.004; B vs C, P = 0.023), but fewer smoked (A vs C, P = 0.027; B vs C, P = 0.020). Patients in group C had a larger proportion of poorly differentiated cancer (A vs C, P = 0.002; B vs C, P = 0.012). No differences in glucose metabolism were found among the different histological types.

Conclusions

We further support the notion that diabetes duration >24 months might not be cancer related. Older and fatter PC patients were more likely to develop hyperglycemia. More patients with long‐standing diabetes had poor tumor differentiation. We speculate that smoking and alcohol intake might advance PC onset.     

Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes

Aims/hypothesis  

This study examined sex-related differences in the cumulative risk of proliferative retinopathy (PR) and end-stage renal disease (ESRD) over 40 years of duration of type 1 diabetes according to age at diabetes onset.     

Insulin deficiency with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes

Aims/Introduction

Patients with a total pancreatectomy and type 1 diabetes are similar in regard to absolute insulin deficiency, but different in regard to glucagon, providing a unique opportunity to study the contribution of glucagon to glucose metabolism in an insulin‐dependent state. The aim of the present study was to investigate the contribution of glucagon to glucose homeostasis in complete insulin deficiency in vivo.

Methods

A total of 38 individuals with a complete lack of endogenous insulin (fasting C‐peptide <0.0066 nmol/L) and whose glycemic control was optimized with an insulin pump during hospitalization were retrospectively studied. The basal insulin requirement, time‐to‐time adjustment of the basal insulin infusion rate, prandial insulin requirement and fasting plasma glucagon were compared between patients with a total pancreatectomy (n = 10) and those with type 1 diabetes (n = 28) after achievement of optimal glycemic control.

Results

Total daily insulin (P = 0.03) and basal insulin (P = 0.000006), but not prandial insulin requirements, were significantly lower in total pancreatectomy patients than in type 1 diabetes patients. The basal percentage (basal insulin/total daily insulin) was also significantly lower in total pancreatectomy patients than in type 1 diabetes patients (15.8 ± 7.8 vs 32.9 ± 10.1%, P = 0.00003). An increase in the insulin infusion rate early in the morning was not necessary in most patients with a pancreatectomy. The fasting plasma glucagon concentration was significantly lower in total pancreatectomy patients than in type 1 diabetes patients (P = 0.00007), and was positively correlated with the basal insulin requirement (P = 0.038).

Conclusions

The difference in insulin requirements between total pancreatectomy and type 1 diabetes patients suggests a contribution of glucagon to the basal insulin requirement and dawn phenomenon.     

Micro‐ribonucleic acid‐binding site variants of type 2 diabetes candidate loci predispose to gestational diabetes mellitus in Chinese Han women

Aims/Introduction

Emerging evidence has suggested that the genetic background of gestational diabetes mellitus (GDM) was analogous to type 2 diabetes mellitus. In contrast to type 2 diabetes mellitus, the genetic studies for GDM were limited. Accordingly, the aim of the present study was to extensively explore the influence of micro‐ribonucleic acid‐binding single‐nucleotide polymorphisms (SNPs) in type 2 diabetes mellitus candidate loci on GDM susceptibility in Chinese.

Materials and Methods

A total of 839 GDM patients and 900 controls were enrolled. Six micro‐ribonucleic acid‐binding SNPs were selected from 30 type 2 diabetes mellitus susceptibility loci and genotyped using TaqMan allelic discrimination assays.

Results

The minor allele of three SNPs, PAX4 rs712699 (OR 1.366, 95% confidence interval 1.021–1.828, P = 0.036), KCNB1 rs1051295 (OR 1.579, 95% confidence interval 1.172–2.128, P = 0.003) and MFN2 rs1042842 (OR 1.398, 95% confidence interval 1.050–1.862, P = 0.022) were identified to significantly confer higher a risk of GDM in the additive model. The association between rs1051295 and increased fasting plasma glucose (b = 0.006, P = 0.008), 3‐h oral glucose tolerance test plasma glucose (b = 0.058, P = 0.025) and homeostatic model assessment of insulin resistance (b = 0.065, P = 0.017) was also shown. Rs1042842 was correlated with higher 3‐h oral glucose tolerance test plasma glucose (b = 0.056, P = 0.028). However, no significant correlation between the other included SNPs (LPIN1 rs1050800, VPS26A rs1802295 and NLRP3 rs10802502) and GDM susceptibility were observed.

Conclusions

The present findings showed that micro‐ribonucleic acid‐binding SNPs in type 2 diabetes mellitus candidate loci were also associated with GDM susceptibility, which further highlighted the similar genetic basis underlying GDM and type 2 diabetes mellitus.     

Genetic differences between type 1 diabetes with and without other autoimmune diseases

Background

Clusters of autoimmune diseases (ADs) are present in some people with type 1 diabetes. This clustering suggests the existence of common genetic backgrounds for abnormal autoimmunity in these individuals. However, the genetic differences between type 1 diabetes patients with and without other ADs are not well known.

Methods

To investigate the clinical background and genetic differences between type 1 diabetes patients with and without other ADs, single nucleotide polymorphisms (SNPs) in the CTLA4, SUMO4, PTPN22, IRF5, STAT4, and BLK genes were analysed by using either a TaqMan assay or direct sequencing. The frequencies of alleles, genotypes of each gene, and the human leukocyte antigen (HLA) haplotype were analysed to investigate differences among 3 groups: type 1 diabetes with systemic ADs (group A), type 1 diabetes with other organ‐specific ADs (group B), and type 1 diabetes without other ADs (group C).

Results

The frequency of the C allele in the ‐1123G > C SNP in the PTPN22 gene promoter was significantly higher in groups A and B than in group C (P = .0258 and .0207, respectively). The allele frequencies of the other SNPs were comparable. The frequency of HLA DRB1*0405‐DQB1*0401 was significantly higher in groups A and B than in group C (P = .021 and .0395, respectively).

Conclusions

The ‐1123G > C SNP in the PTPN22 gene promoter and HLA DRB1*0405‐DQB1*0401 might influence the concurrence of systemic and organ‐specific ADs in patients with type 1 diabetes.     

Diabetes mellitus and risk of dementia: A meta‐analysis of prospective observational studies

Aims/Introduction

The aim of the present study was to investigate the association between diabetes and the risk of all type dementia (ATD), Alzheimer's disease (AD) and vascular dementia (VaD).

Materials and Methods

Prospective observational studies describing the incidence of ATD, AD and VaD in patients with diabetes mellitus were extracted from PubMed, EMBASE and other databases up to January 2012. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random‐effects model. Subgroup analyses and sensitivity analysis were also carried out.

Results

A total of 28 studies contributed to the analysis. Pooled RR of developing ATD (n = 20) was 1.73 (1.65–1.82, I² = 71.2%), AD (n = 20) was 1.56 (1.41–1.73, I² = 9.8%) and VaD (n = 13) was 2.27 (1.94–2.66, I² = 0%) in patients with diabetes mellitus. Higher and medium quality studies did not show any significant difference for pooled RR for ATD, AD or VaD. Sensitivity analyses showed robustness of pooled RR among ATD, AD and VaD, showing no single study had a major impact on pooled RR.

Conclusions

The results showed a 73% increased risk of ATD, 56% increase of AD and 127% increase of VaD in diabetes patients.     

Long-term impact of weight loss for people with overweight but not obesity,and with type 2 diabetes: 10-year outcomes of a randomized trial of gastric band surgery

Aim

Randomized trials reporting 5-year outcomes have shown bariatric surgery  to induce diabetes remission and improve cardiovascular risk. However, the longer-term effects of surgery are uncertain, with only one randomized trial reporting 10-year diabetes outcomes in people with obesity. We aimed to compare 10-year diabetes outcomes of people who are overweight but not obese, randomly assigned to receive either multidisciplinary diabetes care, or multidisciplinary diabetes care combined with gastric band (GB) surgery.

Methods

Between 2009 and 2011, 51 adults were randomized. After 5 years, they were discharged to receive community care and reassessed after 10 years. The primary outcome was diabetes remission, defined as glycated haemoglobin (HbA1c) <6.5% (48 mmol/mol) without glucose-lowering medication.

Results

Forty-one participants (20 medical and 21 GB) completed the 10-year assessment. The median (Q1, Q3) weight loss in the GB group was 9.8 (6.7, 16.3)% at 10 years compared with 5.6 (3.4, 7.6)% in the medical group (median difference 4.2%; p = .008). Diabetes remission occurred in five GB participants and no medical participants (relative risk 0.76, 95% CI: 0.55-0.93, p = .048). GB participants used fewer glucose-lowering medications at 10 years but HbA1c, fasting glucose, calculated cardiovascular risk, quality-of-life and incident diabetes complications did not differ significantly between the groups.

Conclusion

When compared with medical care, GB surgery achieved greater weight loss and modestly increased the likelihood of diabetes remission. However, it did not improve HbA1c, cardiovascular risk or quality of life.     

External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants?

Aims

To describe the proportion of people with Type 2 diabetes living in Scotland who meet eligibility criteria for inclusion in several large randomized controlled trials of glycaemic control to inform physicians and guideline developers about the generalizibility of trial results.

Methods

A literature review was performed to identify large trials assessing the impact of glycaemic control on risk of macrovascular disease. Inclusion and exclusion criteria from each trial were applied to data on the population of people with a diagnosis of Type 2 diabetes living in Scotland in 2008 (n = 180 590) in a population‐based cross‐sectional study and the number and proportion of people eligible for each trial was determined.

Results

Seven trials were identified. The proportion of people with Type 2 diabetes who met the eligibility criteria for the trials ranged from 3.5 to 50.7%. Trial participants were younger at age of diagnosis of diabetes and at time of trial recruitment than in the Scottish study population. The application of upper age criteria excluded the largest proportion of patients, with up to 39% of people with Type 2 diabetes ineligible for a trial with the most stringent criteria based on age alone.

Conclusions

We found that many of the large trials of glycaemic control among people with Type 2 diabetes have limited external validity when applied to a population‐based cohort of people with Type 2 diabetes. In particular, the age distribution of trial participants often does not reflect that of people with Type 2 diabetes in a contemporary British population.     

Case fatality rates after first acute coronary syndrome in persons treated for type 2 diabetes show an improving trend

Aims/hypothesis  

We analysed whether the prognosis of a first acute coronary syndrome (ACS) in patients treated for type 2 diabetes has improved. We also compared the trends in patients with and without diabetes.     

Increased prevalence of non-alcoholic fatty liver disease in European women with a history of gestational diabetes

Aims/hypothesis  

Non-alcoholic fatty liver disease (NAFLD) is common in type 2 diabetes but it is unknown whether NAFLD is prevalent in European women at risk of type 2 diabetes. We studied the prevalence of, and risk factors for, NAFLD in European women with previous gestational diabetes (GDM) at high risk of type 2 diabetes.     

Ischemic heart disease is associated with vertebral fractures in patients with type 2 diabetes mellitus

Aims/Introduction

Discordant results about the relationship between diabetes complications and the risk of fragility fractures have been reported. Our aims were to analyze the factors related to morphometric vertebral fractures (VFs) in patients with type 2 diabetes mellitus, and to explore the association between the presence of VFs and the main cardiovascular risk factors.

Materials and Methods

We carried out a cross‐sectional study including 123 patients with type 2 diabetes mellitus, and in 72 of these patients we recorded data about the risk factors for VFs and comorbidities of diabetes including diabetes‐related microvascular disease and cardiovascular disease.

Results

In the crude analysis, diabetic retinopathy (odds ratio [OR] 4.09, 95% confidence interval [CI] 1.01–12.5), ischemic heart disease (OR 5.02, 95% CI 1.1–9.7) and waist circumference (OR 1.06, 95% CI 1.006–1.114) were related to VFs. In the full model (adjusted for age, sex, body mass index), ischemic heart disease was the only determinant of VF (OR 3.33, CI 1.02–10.91, P = 0.047); whereas diabetic retinopathy did not reached significance (OR 2.27, CI 0.71–7.27, P = 0.16).

Conclusions

In summary, ischemic heart disease is associated with an increased risk of VFs in type 2 diabetes mellitus.     

Effect of type 2 diabetes on mortality risk associated with end-stage kidney disease

Aims/hypothesis  

Patients with end-stage kidney disease (ESKD) and patients with diabetes mellitus experience higher mortality rates than the general population. Whether ESKD imparts the same excess in mortality risk for those with diabetes as it does for those without diabetes is unknown.     

IFN-γ and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes

Aims/hypothesis  

Islet antibody-negative first-degree relatives of type 1 diabetes patients have a very low risk of developing diabetes. We studied the balance between IFN-γ (proinflammatory) and IL-10 (regulatory) T cell responses in these participants.