Anthony H. Barnett

Congenital leptin deficiency is associated with severe early-onset obesity in humans.

The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptins role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.

New treatments in type 2 diabetes: a focus on the incretin‐based therapies

The demonstration that the incretin hormone glucagon‐like peptide 1 can improve glycaemic control in patients with type 2 diabetes has led to the rapid development during the last decade of promising new classes of agent for the management of type 2 diabetes. These agents possess a range of physiological effects that are associated with improved glycaemic control in diabetes including stimulation of glucose‐dependent insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, and reduction of food intake. In addition, preclinical studies suggest that incretin‐based therapies may improve β‐cell function via enhancement of β‐cell mass and induction of genes important for differentiated β‐cell function. Exenatide, and the dipeptidyl peptidase‐4 inhibitors, sitagliptin and vildagliptin are already approved, and liraglutide is currently completing Phase 3 trials. As these agents and standard oral therapies for type 2 diabetes lower glucose levels through different, but potentially complementary mechanisms, their use in combination should provide effective, potentially additive, glycaemic control. The incretin‐based therapies also offer other advantages such as weight loss with exenatide and liraglutide, a reduced risk of hypoglycaemia, and as suggested by preclinical studies, a potential β‐cell preserving effect. Long‐term outcome and safety data are not available for these agents, but they appear generally well‐tolerated in comparison with existing therapies for type 2 diabetes. The multiple underlying glucose‐lowering actions of the incretin‐based therapies, as well as a lack of weight gain or even weight loss, make these important new additions to available antidiabetic agents expanding the treatment options available for patients.

Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus

The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1–kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By ‘cross–match’ haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent–of–origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.

Management of type 2 diabetes: new and future developments in treatment

The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium-glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11β-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery.

Resistin, central obesity, and type 2 diabetes

Resistin, an adipocyte-derived cytokine, causes insulin resistance and glucose intolerance in mice. We investigated whether resistin expression was higher in human abdominal adipose tissue than other adipose tissue depots. We extracted RNA from 32 adipose tissue samples (13 subcutaneous abdominal, seven omentum, six thigh, and six breast). Quantitative PCR was used to determine resistin mRNA expression. Resistin mRNA concentrations were similar in both the subcutaneous abdominal and omental depots. The abdominal depots showed a 418% increase in resistin mRNA expression compared with the thigh. Increased resistin expression in abdominal fat could explain the increased risk of type 2 diabetes associated with central obesity.

Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10−4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10−8 to P = 1.9 × 10−11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10−4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.

Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus.

Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical‐scavenging antioxidant activity of serum from 28 patients with insulin‐dependent diabetes mellitus and 24 patients with non‐insulin‐dependent diabetes mellitus uncomplicated by vascular disease with age‐matched non‐diabetic control subjects. Patients with insulin‐dependent diabetes had significantly reduced total antioxidant activity (320.2 ± 11.3 vs. 427.5 ± 19.2 μmol L−1; P < 0.001). This was attributable to lower urate (209.4 ± 10.4 vs. 297.1 ± 16.7 μmol L−1; P < 0.001) and vitamin C levels (63.6 ± 6.0 vs. 87.5 ± 4.9 μmol L−1; P < 0.01). Patients with non‐insulin‐dependent diabetes had lower total antioxidant activity than age‐matched control subjects (433.8 ± 25.4 vs. 473.9 ± 30.2 μmol L−1; NS), reflecting lower urate (299.5 ± 19.4 vs. 324.8 ± 21.4 μmol L−1; NS) and vitamin C levels (38.6 ± 5.7 vs. 58.5 ± 5.3 μmol L−1; P < 0.05). Multiple regression analysis showed that urate, vitamin C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.

A search for type 1 diabetes susceptibility genes in families from the United Kingdom

Genetic analysis of a mouse model of major histocompatability complex (MHC)-associated autoimmune type 1 (insulin-dependent) diabetes mellitus (IDDM) has shown that the disease is caused by a combination of a major effect at the MHC and at least ten other susceptibility loci elsewhere in the genome. A genome-wide scan of 93 affected sibpair families (ASP) from the UK (UK93) indicated a similar genetic basis for human type 1 diabetes, with the major genetic component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease (λs = 2.5; Refs 3,4). In the present report, we have analysed a further 263 multiplex families from the same population (UK263) to provide a total UK data set of 356 ASP families (UK356). Only four regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded at λs = 3 and lod = –2, of which two showed evidence of linkage: chromosome 10p13–p11 (maximum lod score (MLS) = 4.7, P = 3 × 10 –6, λs = 1.56) and chromosome 16q22–16q24 (MLS = 3.4, P = 6.5 × 10–5, λ s = 1.6). These and other novel regions, including chromosome 14q12–q21 and chromosome 19p13–19q13, could potentially harbour disease loci but confirmation and fine mapping cannot be pursued effectively using conventional linkage analysis. Instead, more powerful linkage disequilibrium-based and haplotype mapping approaches must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage.

Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study

Diabet. Med. 29, 682–689 (2012)

DPP-4 inhibitors and their potential role in the management of type 2 diabetes

The dipeptidyl peptidase 4 (DPP‐4) inhibitors enhance the bodys own ability to control blood glucose by increasing the active levels of incretin hormones in the body. Their mechanism of action is distinct from any existing class of oral glucose‐lowering agents. They control elevated blood glucose by triggering pancreatic insulin secretion, suppressing pancreatic glucagon secretion, and signalling the liver to reduce glucose production. The leading DPP‐4 inhibitors have shown clinically significant HbA1c reductions up to 1 year of treatment and offer many potential advantages over existing diabetes therapies including a low risk of hypoglycaemia, no effect on body weight, and the potential, based on animal and in vitro studies, for the regeneration and differentiation of pancreatic β‐cells. They are efficacious as monotherapy and also in combination with commonly prescribed antidiabetic agents and are suitable for once‐daily oral dosing. Consequently, many DPP‐4 inhibitors such as vildagliptin (Galvus; LAF‐237), sitagliptin (Januvia; MK‐0431), and saxagliptin (BMS‐477118) have advanced into late‐stage human clinical trials.