Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy

Aims/hypothesis

Our aim was to study whether glycaemic control differs between individuals with latent autoimmune diabetes in adults (LADA) and patients with type 2 diabetes, and whether it is influenced by time on insulin therapy.

Methods

We performed a retrospective study of 372 patients with LADA (205 men and 167 women; median age 54 years, range 35–80 years) from Swedish cohorts from Skåne (n?=?272) and Västerbotten (n?=?100). Age- and sex-matched patients with type 2 diabetes were included as controls. Data on the use of oral hypoglycaemic agents (OHAs), insulin and insulin–OHA combination therapy was retrieved from the medical records. Poor glycaemic control was defined as HbA_1c ≥7.0% (≥53 mmol/mol) at follow-up.

Results

The individuals with LADA and with type 2 diabetes were followed for an average of 107 months. LADA patients were leaner than type 2 diabetes patients at diagnosis (BMI 27.7 vs 31.0 kg/m²; p?<?0.001) and follow-up (BMI 27.9 vs 30.2 kg/m²; p?<?0.001). Patients with LADA had been treated with insulin for longer than those with type 2 diabetes (53.3 vs 28.8 months; p?<?0.001). There was no significant difference between the patient groups with regard to poor glycaemic control at diagnosis, but more patients with LADA (67.8%) than type 2 diabetes patients (53.0%; p?<?0.001) had poor glycaemic control at follow-up. Patients with LADA had worse glycaemic control at follow-up compared with participants with type 2 diabetes (OR?=?1.8, 95% CI 1.2, 2.7), adjusted for age at diagnosis, HbA_1c, BMI at diagnosis, follow-up time and duration of insulin treatment.

Conclusions/interpretation

Individuals with LADA have worse glycaemic control than patients with type 2 diabetes despite a longer time on insulin therapy.     

Effects of a Single Bout of Interval Hypoxia on Cardiorespiratory Control and Blood Glucose in Patients With Type 2 Diabetes

OBJECTIVE

Hypoxia may cause functional autonomic imbalance in diabetes. Intermittent hypoxia (IH), a technique improving the adaptation to hypoxia, might improve cardiorespiratory reflexes and, ultimately, blood glucose concentrations in patients with type 2 diabetes. We tested whether a single bout of IH could initiate a long-lasting response potentially leading to better adaptation to hypoxia.

RESEARCH DESIGN AND METHODS

In 14 patients with type 2 diabetes without autonomic complications, we measured blood pressure, heart rate, oxygen saturation, chemoreflex (hypoxic and hypercapnic ventilatory responses, ventilatory recruitment threshold), and baroreflex sensitivity before, immediately after, and 3 and 6 h after a 1-h single bout of IH (6-min breathing of 13% oxygen mixture 5 times each separated by 6-min recovery). The measurements were repeated on a placebo day (at least 1 week apart, in random sequence) when subjects were only breathing room air (single-blind protocol).

RESULTS

IH significantly increased hypercapnic ventilatory responses and reduced ventilatory recruitment threshold, and increased oxygen saturation and blood pressures, whereas increases in heart rate variability and baroreflex sensitivity were not significant. Blood glucose significantly decreased after IH. No such changes were observed during the placebo day, except an increase in oxygen saturation. Some of the effects lasted 3 h after IH, and some even persisted until 6 h after IH.

CONCLUSIONS

A single bout of IH induced an initial adaptation to hypoxia, with improvement in cardiorespiratory reflexes and reduction in blood glucose. Patients with type 2 diabetes could potentially benefit from the application of a full (>2 weeks) IH intervention.In diabetes, abnormalities of the autonomic nervous system (ANS) represent one important complication of the disease (1) because it can predispose to severe cardiovascular events (2,3). ANS dysfunction is not exclusively induced by anatomic lesions but has an important functional component (4). Low oxygen content (hypoxia), described in most organs and tissues of diabetic patients (5–9), recently has been suggested as one cause of ANS abnormalities (10,11). As a consequence, improvement of existing hypoxia might improve autonomic abnormalities that, in turn, also might have consequences on glucose metabolism.One possible strategy to improve hypoxia could be the application of intermittent hypoxia (IH). IH improves exercise capacity in athletes, improves the acclimatization to high altitude in climbers (12,13), and improves ANS in various patients (14,15). The technique consists of intermittent exposures to hypoxic stimuli (3–5 times per day, lasting at least 5–6 min, and spaced at least by 5–6 min) repeated over 2–3 weeks. The principle of the method is like any other type of training: a given stress (here, hypoxia), if appropriately administered and spaced in time, creates a counter-regulatory response that lasts longer and, when repeated a sufficient number of times, leads to a sustained “training” effect (16). IH could increase resting oxygen saturation by increasing the ventilation and the chemoreflexes and, consequently, could reduce the sympathetic activation associated with hypoxia, as previously shown in patients with chronic bronchitis (17).However, until now the effects of IH in patients with type 2 diabetes are unknown, even though respiratory and cardiovascular reflexes (18–24) and molecular responses to hypoxia (25) have been found to be generally impaired. Therefore, performing a short course of IH might initiate a chain of events that may eventually lead to an “acclimatization” process (when prolonging IH to >1 day). The consequence of relieving hypoxia should be restoration and correction of the cardiorespiratory reflexes.If positive results could be found from this initial study performed in type 2 diabetic subjects without complications, then performing a full training period of IH could be justified in diabetes to test whether this intervention is able to prevent the development of diabetes complications.     

Osteoprotegerin Is an Independent Predictor of Vascular Events in Finnish Adults With Type 1 Diabetes

OBJECTIVEOsteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D).RESULTSOnly patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01–1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13–1.88]; P = 0.004) during follow-up.CONCLUSIONSWe showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.Arterial calcification is strongly associated with the development and progression of vascular stiffening and arteriosclerosis leading to cardiovascular disease (CVD). This process is accelerated in patients with diabetes or chronic kidney disease (CKD) and especially in those with both (1). Many of the key regulators of bone mineralization also appear to be key mediators of osteogenic transformation of vascular smooth muscle cells and arterial calcification in diabetes (2,3). One of the most well known is osteoprotegerin (OPG) (4,5). OPG concentrations are positively correlated with coronary calcification (6), vascular stiffness (7), and the presence of unstable plaque (8) in nondiabetic individuals and an increased risk of cardiovascular (CV) mortality in patients with diabetes (9,10). In this study, we further explore the association between circulating concentrations of OPG and CV outcomes in a large well-characterized cohort of patients with type 1 diabetes (T1D) exploring mortality, coronary, stroke, and amputation events.     

Interaction between prenatal growth and high-risk genotypes in the development of type 2 diabetes

Aims/hypothesis  Early environmental factors and genetic variants have been reported to be involved in the pathogenesis of type 2 diabetes. The aim of this study was to investigate whether there is an interaction between birthweight and common variants in the TCF7L2, HHEX, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B and JAZF1 genes in the risk of developing type 2 diabetes. Methods  A total of 2,003 participants from the Helsinki Birth Cohort Study, 311 of whom were diagnosed with type 2 diabetes by an OGTT, were genotyped for the specified variants. Indices for insulin sensitivity and secretion were calculated. Results  Low birthweight was associated with type 2 diabetes (p = 0.008) and impaired insulin secretion (p = 0.04). Of the tested variants, the risk variant in HHEX showed a trend towards a low birthweight (p = 0.09) and the risk variant in the CDKN2A/2B locus was associated with high birthweight (p = 0.01). The TCF7L2 risk allele was associated with increased risk of type 2 diabetes. Pooling across all nine genes, each risk allele increased the risk of type 2 diabetes by 11%. Risk variants in the HHEX, CDKN2A/2B and JAZF1 genes interacted with birthweight, so that the risk of type 2 diabetes was highest in those with lower birthweight (p ≤ 0.05). The interaction was also present in the pooled data. Conclusions/interpretation  Low birthweight might affect the strength of the association of some common variants (HHEX, CDKN2A/2B and JAZF1) with type 2 diabetes. These findings need to be replicated in independent cohorts. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. An erratum to this article can be found at     

Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT study)

Aims/hypothesis Recent genome-wide association studies performed in selected patients and control participants have provided strong support for several new type 2 diabetes susceptibility loci. To get a better estimation of the true risk conferred by these novel loci, we tested a completely unselected population of type 2 diabetes patients from a Norwegian health survey (the HUNT study). Methods We genotyped single nucleotide polymorphisms (SNPs) in PKN2, IGFBP2, FLJ39370 (also known as C4ORF32), CDKAL1, SLC30A8, CDKN2B, HHEX and FTO using a Norwegian population-based sample of 1,638 patients with type 2 diabetes and 1,858 non-diabetic control participants (the HUNT Study), for all of whom data on BMI, WHR, cholesterol and triacylglycerol levels were available. We used diabetes, measures of obesity and lipid values as phenotypes in case-control and quantitative association study designs. Results We replicated the association with type 2 diabetes for rs10811661 in the vicinity of CDKN2B (OR 1.20, 95% CI: 1.06–1.37, p = 0.004), rs9939609 in FTO (OR 1.14, 95% CI: 1.04–1.25, p = 0.006) and rs13266634 in SLC30A8 (OR 1.20, 95% CI: 1.09–1.33, p = 3.9 × 10⁻⁴). We found borderline significant association for the IGFBP2 SNP rs4402960 (OR 1.10, 95% CI: 0.99–1.22). Results for the HHEX SNP (rs1111875) and the CDKAL1 SNP (rs7756992) were non-significant, but the magnitude of effect was similar to previous estimates. We found no support for an association with the less consistently replicated FLJ39370 or PKN2 SNPs. In agreement with previous studies, FTO was most strongly associated with BMI (p = 8.4 × 10⁻⁴). Conclusions/interpretation Our data show that SNPs near IGFBP2, CDKAL1, SLC30A8, CDKN2B, HHEX and FTO are also associated with diabetes in non-selected patients with type 2 diabetes. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus

Aims/hypothesis

Homozygosity for a five leucine repeat (5L–5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L–5L is associated with mortality; (2) there is an interaction of 5L–5L with DN or sex for prediction of mortality; and (3) 5L–5L is associated with progression to end-stage renal disease (ESRD).

Methods

In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria <30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation.

Results

The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L–5L died compared with 182 patients (13.8%) with other genotypes (p?=?0.99). There was no significant interaction of 5L–5L with DN for prediction of mortality (p?=?0.57), but a trend towards interaction with sex (p?=?0.08). In patients with DN, HR for ESRD in 5L–5L vs other genotypes was not constant over time, with increased risk for 5L–5L beyond 8 years of follow-up (p?=?0.03).

Conclusions/interpretation

CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.     

Effects of weight loss on substrate oxidation, energy expenditure, and insulin sensitivity in obese individuals.

To evaluate the effect of weight loss on substrate oxidation, energy expenditure, and insulin sensitivity we studied 12 obese subjects (body mass index 33.4 +/- 1.1) before and after 6 wk of a very-low-calorie diet (VLCD) with euglycemic insulin clamp in combination with indirect calorimetry. Body weight decreased from 105.3 +/- 4.6 to 94.1 +/- 4.0 kg (P less than 0.001) and fat mass from 47.2 +/- 3.6 to 37.7 +/- 3.0 kg (P less than 0.001). Total glucose disposal during insulin clamp increased from 30.4 +/- 4.3 to 38.4 +/- 4.4 mumol.kg lean body mass (LBM)-1.min-1 (P less than 0.05), insulin-stimulated glucose oxidation from 14.3 +/- 4.6 to 19.1 +/- 1.4 mumol.kg LBM-1.min-1 (P less than 0.05), and non-oxidative glucose metabolism from 16.0 +/- 3.8 to 19.3 +/- 3.6 mumol.kg LBM-1.min-1 (NS). Lipid oxidation decreased in the basal state (P less than 0.05) and during the insulin clamp (P less than 0.01). The basal rate of energy expenditure decreased from 99.1 +/- 4.6 to 88.5 +/- 2.7 kJ.kg LBM-1.min-1 (P less than 0.05) after weight reduction. A reduction in fat mass achieved by VLCD is associated with reduced lipid oxidation and, because of substrate competition, enhanced glucose oxidation. The physiological consequence is improved insulin sensitivity.     

The cross-sectional associations between sense of coherence and diabetic microvascular complications,glycaemic control,and patients' conceptions of type 1 diabetes

Background  

Sense of coherence (SOC) has been associated with various self-care behaviours in the general population. As the management of type 1 diabetes heavily relies on self-management, the SOC concept could also prove important in this population. This paper is a report of a study conducted among patients with type 1 diabetes to assess the associations between SOC and glycaemic control, microvascular complications, and patients' conceptions of their disease.     

Association of Microsatellite Polymorphisms of the Human 14q13.2 Region with Type 2 Diabetes Mellitus in Latvian and Finnish Populations

A polymorphic microsatellite in intron 6 of the human proteasome core particle PSMA6 gene (HSMS006), and four other microsatellites localized upstream on human chromosome 14q13.2 (HSMS801, HSMS702, HSMS701, HSMS602), were genotyped in 104 type 2 diabetic patients and 129 age-matched control subjects from Latvia and replicated in 91 type 2 diabetic patients and 88 age-matched healthy control subjects from the Botnia Study in Finland. In type 2 diabetic patients from both populations the HSMS006 (TG)22 allele was two times more frequent compared to the control group. In the Latvian population the (CAA)8 allele of the HSMS602 marker was less frequent in the diabetic group, as was the (AC)24 allele of microsatellite HSMS801. Allele frequencies of the HSMS701 and 702 repeats were similar in healthy controls and type 2 diabetic patients. In conclusion, our data suggest that variants in the PSMA6 gene on chromosome 14q13.2 are associated with type 2 diabetes.