OBJECTIVE—Latent autoimmune diabetes in adults (LADA) is often considered a slowly progressing subtype of type 1 diabetes, although the clinical picture more resembles type 2 diabetes. One way to improve classification is to study whether LADA shares genetic features with type 1 and/or type 2 diabetes. RESEARCH DESIGN AND METHODS—To accomplish this, we studied whether LADA shares variation in the HLA locus or INS VNTR and PTPN22 genes with type 1 diabetes or the TCF7L2 gene with type 2 diabetes in 361 LADA, 718 type 1 diabetic, and 1,676 type 2 diabetic patients, as well as 1,704 healthy control subjects from Sweden and Finland. RESULTS—LADA subjects showed, compared with type 2 diabetic patients, increased frequency of risk for the HLA-DQB1 *0201/*0302 genotype (27 vs. 6.9%; P < 1 × 10−6), with similar frequency as with type 1 diabetes (36%). In addition, LADA subjects showed higher frequencies of protective HLA-DQB1 *0602(3)/X than type 1 diabetic patients (8.1 vs. 3.2%, P = 0.003). The AA genotype of rs689, referring to the class I allele in the INS VNTR, as well as the CT/TT genotypes of rs2476601 in the PTPN22 gene, were increased both in type 1 diabetic (P = 3 × 10−14 and P = 1 × 10−10, respectively) and LADA (P = 0.001 and P = 0.002) subjects compared with control subjects. Notably, the frequency of the type 2 diabetes–associated CT/TT genotypes of rs7903146 in the TCF7L2 were increased in LADA subjects (52.8%; P = 0.03), to the same extent as in type 2 diabetic subjects (54.1%, P = 3 × 10−7), compared with control subjects (44.8%) and type 1 diabetic subjects (43.3%). CONCLUSIONS—LADA shares genetic features with both type 1 (HLA, INS VNTR, and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes.

Aims/hypothesis Mutations in the hepatocyte nuclear factor 1-α gene (HNF-1α, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes. Subjects and methods We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1α gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. Results Certain combinations of the I27L and A98V polymorphisms in the HNF-1α gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n=2,293; p=0.003). In a new case-control (n=1,511 and n=2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR)=1.5 ( p=0.002; multiple logistic regression), particularly in

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It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1␣, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1␣ with glucose-related traits.

OBJECTIVE -Impaired muscular mitochondrial function is related to common insulin resistance in type 2 diabetes. Mitochondrial diseases frequently lead to diabetes, which is mostly attributed to defective ␤-cell mitochondria and secretion.RESEARCH DESIGN AND METHODS -We assessed muscular mitochondrial function and lipid deposition in liver (hepatocellular lipids [HCLs]) and muscle (intramyocellular lipids [IMCLs]) using 31 P/ 1 H magnetic resonance spectroscopy and insulin sensitivity and endogenous glucose production (EGP) using hyperinsulinemic-euglycemic clamps combined with isotopic tracer dilution in one female patient suffering from MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome and in six control subjects.RESULTS -The MELAS patient showed impaired insulin sensitivity (4.3 vs. 8.6 Ϯ 0.5 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and suppression of EGP (69 vs. 94 Ϯ 1%), and her baseline and insulin-stimulated ATP synthesis were reduced (7.3 and 8.9 vs. 10.6 Ϯ 1.0 and 12.8 Ϯ 1.3 mol ⅐ l Ϫ1 ⅐ min Ϫ1 ) compared with those of the control subjects. HCLs and IMCLs were comparable between the MELAS patient and control subjects.CONCLUSIONS -Impairment of muscle mitochondrial fitness promotes insulin resistance and could thereby contribute to the development of diabetes in some patients with the MELAS syndrome. Diabetes Care 32:677-679, 2009T he MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome is caused by a maternally inherited mtDNA mutation, resulting in defective cellular respiration. MELAS-associated diabetes has been primarily attributed to insufficient insulin secretion due to mitochondrial dysfunction of pancreatic ␤-cells. Insulinresistant populations show reduced mitochondrial function and increased soleus muscle lipids (intramyocellular lipids [IMCLs]) and liver lipids (hepatocellular lipids [HCLs]) (1). The sequence of events, particularly the possibility of muscle mitochondria leading to insulin resistance, is unclear.RESEARCH DESIGN AND METHODS -One female patient (age 37 years, BMI 24 kg/m 2 , A1C 7.4%) suffering from MELAS (mtDNA mutation A3243G, ϳ60% heteroplasmy in leukocytes, confirmed by PCR amplification) was compared with six nondiabetic female control subjects (age 45 Ϯ 4 years, BMI 24 Ϯ 1 kg/m 2 , A1C 5.2 Ϯ 0.1%). The protocol was approved by an institutional ethics board, and written informed consent was obtained. The patient developed bilateral labyrinthine hypacusis and insulin-dependent diabetes at 26 years of age, underwent surgery for ptosis, and showed vascular lesions in her periventricular white matter.Whole-body insulin sensitivity (insulin-mediated glucose disposal, M) and endogenous glucose production (EGP) were assessed during a normoglycemichyperinsulinemic clamp with infusion of insulin (40 mU ⅐ m body surface area Ϫ1 ⅐ min Ϫ1

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The structural/phase behaviour of self-assembled lyotropic liquid crystals formed in mixtures of a phospholipid and alpha-tocopherol (vitamin E) is presented.

AimsThe aim was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of octreotide subcutaneous (s.c.) depot, a novel octreotide formulation.MethodsThis was a phase I, randomized, open label study. After a single dose of octreotide immediate release (IR) 200 µg, subjects were randomized to one of eight groups to receive three monthly injections of octreotide s.c. depot A 10, 20 or 30 mg, B 30 mg, C 10, 20 or 30 mg or long acting octreotide (octreotide LAR) 30 mg.ResultsOne hundred and twenty-two subjects were randomized. For all depot variants, onset of octreotide release was rapid and sustained for up to 4 weeks. The relative octreotide bioavailability of depot variants vs. octreotide IR ranged from 0.68 (90% confidence interval [CI] 0.61, 0.76) to 0.91 (90% CI 0.81, 1.02) and, vs. octreotide LAR, was approximately four- to five-fold greater: 3.97 (90% CI 3.35, 4.71) to 5.27 ng ml–1 h (90% CI 4.43, 6.27). All depot variants showed relatively rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared with octreotide LAR. A trend of octreotide dose dependence was also indicated from the plasma concentrations and suppression of IGF-1. Maximum inhibition of IGF-1 at steady-state was highest for depot B and C. All depot treatments were well tolerated. The most frequent adverse events were gastrointestinal related.ConclusionsOctreotide s.c. depot provides greater octreotide bioavailability with a more rapid onset and stronger suppression of IGF-1 than octreotide LAR in healthy volunteers.