Diabetes/Metabolism Research and Reviews

The basal insulin analogues glargine and detemir have been subject to a series of trials comparing their clinical profiles to the conventional preparation, neutral protamine Hagedorn (NPH). Careful review of these trials provides opportunities to learn clinically useful lessons about these insulins.

MedLine‐indexed trials comparing glargine or detemir to NPH were scrutinized for control, tolerability and dose data. Separate considerations were made for types 1 and 2 diabetes, and for basal–bolus and basal plus oral glucose‐lowering drugs (OGLD) therapy. Attention was paid to dosing schedules and 24‐h glycaemic profiles.

Collectively, the trials demonstrated an improved balance between glycaemic control and tolerability for both analogues compared to NPH, regardless of regimen and diabetes type. Neither once‐daily glargine nor detemir reliably provides 24‐h basal insulin replacement in all patients with type 1 diabetes; a waning of effect frequently obliges twice‐daily administration. When added to OGLDs in type 2 diabetes, goal‐titrated once‐daily basal insulin generally lowered HbA_1c by ∼1.5%, whereas twice‐daily administration tended to increase insulin dose disproportionately to improvement in control. Hence, adding bolus insulin may be a preferable intensification method to dividing the basal dose. Varying injection time or dividing the basal insulin dose predictably affects the pattern of hypoglycaemia and bolus dose requirements. Morning administration tends to require higher dosing than evening administration.

Scrutiny of trials involving glargine and detemir has increased our understanding of how best to dose basal insulins. An individualized approach is still necessary however, and several questions remain that require further research. Copyright © 2007 John Wiley & Sons, Ltd.

Plasma resistin level is a potential molecular link between obesity and diabetes. Causal role of resistin, type 2 diabetes mellitus (T2DM) and genetic variants have not been thoroughly investigated. Therefore, we conducted a genome‐wide association study (GWAS) to identify quantitative trait loci associated with resistin levels and investigated whether these variants were prospectively associated with the development of metabolic syndrome (MetS) and T2DM in an independent community‐based cohort, the CardioVascular Disease risk FACtors Two‐township Study (CVDFACTS).

We genotyped 382 young‐onset hypertensive (YOH) subjects with Illumina HumanHap550 chips and searched for quantitative trait loci (QTLs) of resistin in the 1^st stage GWAS and confirmed the finding in another 559 YOH subjects. Logistic regression was used to examine the Mendelian randomization effects between genotypes of confirmed QTLs and metabolic outcomes in 3400 subjects of CVDFACTS.

Two single nucleotide polymorphisms (SNP) (rs3745367 and rs1423096) were significantly associated with resistin levels (p = 5.52 × 10⁻¹⁵ and p = 2.54 × 10⁻²⁰) and replicated in another 559 YOH subjects (p = 1.29 × 10⁻³ and p = 1.13 × 10⁻⁷), respectively. The SNP rs1423096 was further associated with the levels of HDL‐C (p = 0.006), the risk of MetS (OR = 2.21, p = 0.0034) and T2DM (OR = 1.62, p = 0.0063) in the CVDFACTS. People with the haplotypes A‐G and G‐G determined by rs3745367 and rs1423096 showed a significantly increased T2DM risk (p = 0.0068 and p = 0.0035, respectively) compared with those with A‐A haplotype.

We have found that rs3745367 and rs1423096 on the RETN gene were significantly associated with resistin levels. However, rs1423096, downstream of RETN, seems to be associated with MetS and T2DM risk more so than rs3745367. The established genotype–disease association points to a causal association of resistin and T2DM. Copyright © 2013 John Wiley & Sons, Ltd.

To explore the predictive performance of the newly established visceral adiposity index for diabetes and prediabetes, as well as the relationships between the visceral adiposity index and the parameters of insulin secretion and action.

Eight hundred twenty‐four first‐degree relatives of individuals with type 2 diabetes who had no known history of abnormal glucose regulation were selected. Diabetes and prediabetes were diagnosed using the standard oral glucose tolerance test.

The visceral adiposity index values were greater for the subjects with prediabetes and diabetes than for those with normal glucose regulation. Among the subjects with normal glucose regulation, the visceral adiposity index was higher for those whose levels were above the median value of the incremental area under the curve for glucose than for the subjects whose levels fell below the median value. The visceral adiposity index was negatively correlated with the homeostasis model assessment of the β‐cell function index (Homa‐β) and with the insulinogenic index (ΔI₃₀/ΔG₃₀). The visceral adiposity index was found to be a valuable predictor of diabetes, but it was not superior to triglyceride levels, waist circumference, or lipid accumulation production.

The first degree relatives of people with type 2 DM who have prediabetes or diabetes have progressively higher visceral adiposity index in association with progressive hyperglycemia, and it was found to correlate with the Homa‐β and the ΔI₃₀/ΔG₃₀. Copyright © 2014 John Wiley & Sons, Ltd.

Acetyl‐CoA carboxylases (ACC) 1 and 2 are central enzymes in lipid metabolism. To further investigate their relevance for the development of obesity and type 2 diabetes, expression of both ACC isoforms was analyzed in obese fa/fa Zucker fatty and Zucker diabetic fatty rats at different ages in comparison to Zucker lean controls.

ACC1 and ACC2 transcript levels were measured by quantitative real‐time polymerase chain reaction in metabolically relevant tissues of Zucker fatty, Zucker diabetic fatty and Zucker lean control animals. Quantitative real‐time polymerase chain reaction was also applied to measure ACC tissue distribution in human tissues. For confirmation on a protein level, quantitative mass spectrometry was used.

Disease‐related transcriptional changes of both ACC isoforms were observed in various tissues of Zucker fatty and Zucker diabetic fatty rats including liver, pancreas and muscle. Changes were most prominent in oxidative tissues of diabetic rats, where ACC2 was significantly increased and ACC1 was reduced compared with Zucker lean control animals. A comparison of the overall tissue distribution of both ACC isoforms in humans and rats surprisingly revealed strong differences. While in rats ACC1 was mainly expressed in lipogenic and ACC2 in oxidative tissues, ACC2 was predominant in oxidative and lipogenic tissues in humans.

Our data support a potential role for both ACC isoforms in the development of obesity and diabetes in rats. However, the finding of fundamental species differences in ACC1 and ACC2 tissue expression might be indicative for different functions of both isoforms in humans and rats and raises the question to which degree these models are predictive for the physiology and pathophysiology of lipid metabolism in humans. Copyright © 2009 John Wiley & Sons, Ltd.

It has been previously shown that hyperglycemia enhances free radical production, inducing oxidative damage, which in its turn activates the death pathways implicated in cell apoptosis and necrosis. But the possible involvement of this pathway in the hyperglycemia‐induced apoptosis of endothelial cells has not yet been reported.

To verify a possible connection between mitochondrial ROS production and apoptosis induced by both stable and oscillating high glucose, SOD, MnTBAP and TTFA was added to HUVEC cell culture medium. We measured nitrotyrosine and 8OHdG as oxidative stress parameters and Bcl‐2 expression and Caspase‐3 expression and activity as apoptosis indicators.

Our results show that hyperglycemia, both stable or oscillating, increases oxidative stress and endothelial cell apoptosis through ROS overproduction at the mitochondrial transport chain level.

The prevention of mitochondrial oxidative damage seems to be a future important therapeutic strategy in diabetes. Copyright © 2006 John Wiley & Sons, Ltd.

Urinary liver‐type fatty acid‐binding protein (L‐FABP) is a useful marker for renal tubulointerstitial injury. Pioglitazone is reported to be effective in early diabetic nephropathy. The aim of the present study was to determine whether pioglitazone affects urinary L‐FABP levels in diabetic nephropathy patients with microalbuminuria.

Sixty‐eight patients with type 2 diabetes and microalbuminuria were randomized to a 12‐month treatment with pioglitazone (30 mg/d, n = 17), glibenclamide (5 mg/d, n = 18), voglibose (0.6 mg/d, n = 17), or nateglinide (270 mg/d, n = 16). Pre‐ and posttreatment urinary albumin excretion (UAE) and urinary L‐FABP concentrations were compared between the four treatment groups and 40 age‐matched healthy subjects.

Pretreatment UAE and urinary L‐FABP levels differed little between the four groups. UAE and urinary L‐FABP levels were significantly greater in the diabetes patients than in the healthy subjects (UAE: p < 0.001; L‐FABP: p < 0.01). After 6 and 12 months, UAE and urinary L‐FABP were significantly lower in the pioglitazone treatment group than in the other treatment groups (UAE: 6 months, p < 0.01 and 12 months, p < 0.001; L‐FABP: 6 months, p < 0.05 and 12 months, p < 0.01).

Pioglitazone, but not glibenclamide, voglibose, or nateglinide, appears to be effective in reducing UAE and the urinary L‐FABP level, suggesting that pioglitazone has a specific role in ameliorating both glomerular and tubulointerstitial lesions associated with early diabetic nephropathy. Copyright © 2006 John Wiley & Sons, Ltd.

There is ethnic variation in the variable number of tandem repeats of the insulin gene (INS VNTR), one of the susceptibility loci for developing type 1 diabetes (T1D). We evaluated the influence of the genotypes and subdivisions of INS VNTR on the development of T1D in Korean subjects.

The study included 352 Korean patients, under the age of 18 years who were diagnosed as having T1D, and 356 control subjects. The insulin − 23HphI A/T single nucleotide polymorphism was used as a marker of class I and III alleles. Surrounding polymorphisms at nucleotide positions + 1127, + 1140, + 2331 and + 2336 were determined as subdivisions of INS VNTR.

Classes I/I, I/III and III/III were observed at frequencies of 95.8, 4.2 and 0% among all subjects, respectively. Class I/III genotype was significantly less frequent in patients with T1D than in controls (2.56 versus 5.90%; odds ratio 0.419; P = 0.039). In a subdivision analysis, the ID/ID genotype was decreased among patients (P = 0.017, adjusted P = 0.085) and the IC allele tended to increase. The frequency of the class I/III genotype was significantly lower among patients who were diagnosed when younger than 7 years of age than in controls (odds ratio 0.115; P = 0.011).

INS VNTR has predominance of class I over class III alleles and is associated with susceptibility to T1D in Koreans. In addition, INS VNTR shows distinctive susceptibility according to the age at the onset of T1D. Copyright © 2010 John Wiley & Sons, Ltd.