Relationship between renal capacity to reabsorb glucose and renal status in patients with diabetes.

AIMS: Interindividual variability in capacity to reabsorb glucose at the proximal renal tubule could contribute to risk of diabetic kidney disease. Our present study investigated, in patients with diabetes, the association between fractional reabsorption of glucose (FRGLU) and degree of renal disease as assessed by urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR). METHODS: FRGLU [1-(glucose clearance/creatinine clearance)] was assessed in 637 diabetes patients attending our tertiary referral centre, looking for correlations between FRGLU and UAE (normo-, micro-, macro-albuminuria) and Kidney Disease: Improving Global Outcomes (KDIGO) eGFR categories: >90 (G1); 90-60 (G2); 59-30 (G3); and<30-16 (G4) mL/min/1.73 m2. Patients were stratified by admission fasting plasma glucose (FPG) into three groups: low (<6mmol/L); intermediate (6-11mmol/L); and high (>11mmol/L). RESULTS: Median (interquartile range, IQR) FRGLU levels were blood glucose-dependent: 99.90% (0.05) for low (n=106); 99.90% (0.41) for intermediate (n=288); and 96.36% (12.57) for high (n=243) blood glucose categories (P<0.0001). Also, FRGLU increased with renal disease severity in patients in the high FPG group: normoalbuminuria, 93.50% (17.74) (n=135); microalbuminuria, 96.56% (5.94) (n=77); macroalbuminuria, 99.12% (5.44) (n=31; P<0.001); eGFR G1, 94.13% (16.24) (n=111); G2, 96.35% (11.94) (n=72); G3 98.88% (7.59) (n=46); and G4, 99.11% (2.20) (n=14; P<0.01). On multiple regression analyses, FRGLU remained significantly and independently associated with UAE and eGFR in patients in the high blood glucose group. CONCLUSION: High glucose reabsorption capacity in renal proximal tubules is associated with high UAE and low eGFR in patients with diabetes and blood glucose levels>11mmol/L.

Dairy consumption is associated with lower plasma dihydroceramides in women from the D.E.S.I.R. cohort.

AIM: In the D.E.S.I.R. cohort, higher consumption of dairy products was associated with lower incidence of hyperglycaemia, and dihydroceramide concentrations were higher in those who progressed to diabetes. Our aim here was to study the relationships between dairy consumption and concentrations of dihydroceramides and ceramides. METHODS: In the D.E.S.I.R. cohort, men and women aged 30-65 years, volunteers from West-Central France, were included in a 9-year follow-up with examinations every 3 years, including food-frequency questionnaires. Two items concerned dairy products (cheese, other dairy products except cheese). At each examination, dihydroceramides and ceramides were determined by mass spectrometry in a cohort subset; in the present study, the 105 people who did not progress to type 2 diabetes were analyzed, as the disorder per se might be a confounding factor. RESULTS: Higher consumption of dairy products (except cheese) was associated with total plasma dihydroceramides during the follow-up, but only in women (P=0.01 for gender interaction). In fact, dihydroceramide levels were lower in women with high vs low consumption (P=0.03), and were significantly increased during follow-up (P=0.01) in low consumers only. There was also a trend for lower ceramides in women with high dairy (except cheese) intakes (P=0.08). Cheese was associated with dihydroceramide and ceramide changes during follow-up (P=0.04 for both), but no clear trend was evident in either low or high consumers. CONCLUSION: These results show that, in women, there is an inverse association between fresh dairy product consumption and predictive markers (dihydroceramides) of type 2 diabetes.

Vasopressin and metabolic disorders: translation from experimental models to clinical use.

Vasopressin has many physiological actions in addition to its well-defined role in the control of fluid homeostasis and urine concentration. An increasing body of evidence suggests that the vasopressin-hydration axis plays a role in glucose homeostasis. This review summarizes the knowledge accumulated over the last decades about the influence of vasopressin in the short-term regulation of glycaemia. It describes the possible role of this hormone through activation of V1a and V1b receptors on liver and pancreas functions and on the hypothalamic-pituitary-adrenal axis. Moreover, we report recent in vivo studies demonstrating the role of vasopressin in the long-term regulation of glycaemia. Indeed, V1a- or double-V1aV1b-receptor knockout mice display significant changes in the glucose and lipid metabolism. In rats, sustained high V1aR activation increases basal glycaemia and aggravates glucose intolerance in obese rats. Finally, the translation from animal findings to human was evidenced by epidemiological and genetic studies that showed that high vasopressin level is a risk factor for hyperglycaemia, metabolic disorders and diabetes.

T-cadherin gene variants are associated with type 2 diabetes and the Fatty Liver Index in the French population.

AIM: Adiponectin is an adipocyte-secreted protein associated with insulin sensitivity. T-cadherin is a receptor for high and medium molecular weight adiponectin. In GWAS, T-cadherin gene (CDH13) polymorphisms are associated with circulating adiponectin levels. This study investigated the associations between genetic variants of CDH13 and type 2 diabetes (T2D), and its related parameters, in a Caucasian population. METHODS: Two polymorphisms of CDH13 (rs11646213 and rs3865188) were genotyped in two French cohorts, a general population from the D.E.S.I.R. study (n=5212) and people with T2D in the DIABHYCAR study (n=3123). Baseline adiponectin levels were measured in D.E.S.I.R. participants who were normoglycaemic at baseline, but hyperglycaemic after 3 years (n=230), and in controls who remained normoglycaemic (n=226) throughout. RESULTS: In a cross-sectional analysis, CDH13 genotype distributions differed between those with and without T2D, with T2D odds ratios (OR) of 1.11 (95% CI: 1.04-1.18; P=0.001) and 0.92 (95% CI: 0.87-0.98; P=0.01) for rs11646213 and rs3865188, respectively. The rs11646213 variant, associated with a higher OR for T2D, was also associated with higher BMI (P=0.03) and HbA1c (P=0.006), and lower plasma adiponectin levels (P=0.03) in the D.E.S.I.R. PARTICIPANTS: Conversely, the rs3865188 variant, associated with a lower OR for T2D, was also associated with lower BMI (P=0.03), HbA1c (P=0.02) and Fatty Liver Index (FLI; P≤0.01), and higher plasma adiponectin levels (P=0.002). Associations with HbA1c, FLI and adiponectin levels persisted after adjusting for BMI. CONCLUSION: CDH13 polymorphisms are associated with prevalent T2D in this French population study. The association may be mediated through effects on BMI and/or plasma adiponectin.

Sex-specific associations of variants in regulatory regions of NADPH oxidase-2 (CYBB) and glutathione peroxidase 4 (GPX4) genes with kidney disease in type 1 diabetes.

Oxidative stress is involved in the pathophysiology of diabetic nephropathy. The superoxide-generating nicotinamide adenine dinucleotide phosphate-oxidase 2 (NOX2, encoded by the CYBB gene) and the antioxidant enzyme glutathione peroxidase 4 (GPX4) play opposing roles in the balance of cellular redox status. In the present study, we investigated associations of single nucleotide polymorphisms (SNPs) in the regulatory regions of CYBB and GPX4 with kidney disease in patients with type 1 diabetes. Two functional SNPs, rs6610650 (CYBB promoter region, chromosome X) and rs713041 (GPX4 3'untranslated region, chromosome 19), were genotyped in 451 patients with type 1 diabetes from a Brazilian cohort (diabetic nephropathy: 44.6%) and in 945 French/Belgian patients with type 1 diabetes from Genesis and GENEDIAB cohorts (diabetic nephropathy: 62.3%). The minor A-allele of CYBB rs6610650 was associated with lower estimated glomerular filtration rate (eGFR) in Brazilian women, and with the prevalence of established/advanced nephropathy in French/Belgian women (odds ratio 1.75, 95% CI 1.11-2.78, p = 0.016). The minor T-allele of GPX4 rs713041 was inversely associated with the prevalence of established/advanced nephropathy in Brazilian men (odds ratio 0.30, 95% CI 0.13-0.68, p = 0.004), and associated with higher eGFR in French/Belgian men. In conclusion, these heterogeneous results suggest that neither CYBB nor GPX4 are major genetic determinants of diabetic nephropathy, but nevertheless, they could modulate in a gender-specific manner the risk for renal disease in patients with type 1 diabetes.

Allelic variations of the vitamin D receptor (VDR) gene are associated with increased risk of coronary artery disease in type 2 diabetics: the DIABHYCAR prospective study.

AIM: Vitamin D deficiency is associated with coronary artery disease (CAD), and the actions of vitamin D are mediated by binding to a specific nuclear vitamin D receptor (VDR). This study investigated the associations of VDR gene variants with CAD in two cohorts of type 2 diabetes patients. METHODS: A cohort of 3137 subjects from the prospective DIABHYCAR study (CAD incidence: 14.8%; follow-up: 4.4 ± 1.3 years) and an independent, hospital-based population of 713 subjects, 32.3% of whom had CAD, were assessed. Three SNPs in the VDR gene were genotyped: rs1544410 (BsmI); rs7975232 (ApaI); and rs731236 (TaqI). RESULTS: In the DIABHYCAR cohort, an association was observed between the A allele of BsmI and incident cases of CAD (HR: 1.16, 95% CI: 1.05-1.29; P = 0.002). Associations were also observed between BsmI (P = 0.01) and TaqI (P = 0.04) alleles and baseline cases of CAD. The AAC haplotype (BsmI/ApaI/TaqI) was significantly associated with an increased CAD prevalence at the end of the study compared with the GCT haplotype (OR: 1.12, 95% CI: 1.02-1.28; P = 0.04). In a cross-sectional study of the independent hospital-based cohort, associations of ApaI (P = 0.009) and TaqI (P = 0.03) alleles with CAD were observed, with similar haplotype results (OR: 1.33, 95% CI: 1.03-1.73; P = 0.03). CONCLUSION: The haplotype comprising the minor allele of BsmI, major allele of ApaI and minor allele of TaqI of VDR (AAC) was associated with an increased risk of CAD in type 2 diabetes patients. This effect was independent of the effects of other known cardiovascular risk factors.

Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study.

CONTEXT: Fat-rich diets are involved in many disorders such as obesity and type 2 diabetes (T2D). The Pro12Ala variant of peroxisome proliferator-activated receptor-γ (PPARγ) is known to modulate body mass index (BMI) and T2D risk. OBJECTIVE: Our aim was to study the interaction effect between PPARγ gene (PPARG) polymorphisms Pro12Ala and 1431C>T and fat intake on incident T2D and BMI in a 9-year prospective cohort drawn from the French general population, the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study (n=4676). METHODS: Nutritional intake was assessed by a food frequency self-questionnaire completed by each participant. Statistical analyses included logistic regression, analysis of covariance and haplotype analysis, with adjustment for confounding variables. RESULTS: A high fat consumption (the third sex-specific tertile of fat intake, as a percentage of energy intake) was associated with an increased T2D risk among ProPro and CC homozygotes (P(interaction)=0.05, odds ratio (OR) (95% confidence interval (95% CI))=1.73 (1.19-2.52) P=0.004 and OR=1.85 (1.27-2.71) P=0.001, respectively) but not in Ala and T carriers. There was a significant interaction effect between Pro12Ala and 1431C>T on BMI (P(interaction)=0.004); Ala was associated with lower BMI in CC homozygotes and with higher BMI in T carriers while the opposite was found for ProPro. There was also an interaction effect between Pro12Ala and dietary fat intake on BMI (P(interaction)=0.02); AlaAla individuals had a higher BMI than Pro carriers among high fat consumers (27.1 ± 1.0 versus 24.9 ± 0.1 for AlaAla and Pro+, respectively). There was no interaction effect between the 1431C>T single-nucleotide polymorphism and fat intake on BMI. CONCLUSION: Our results indicate strong genetic and nutritional interaction effects on BMI and T2D risk at the PPARG locus in a general population.

Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

AIMS/HYPOTHESIS: We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. METHODS: We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. RESULTS: We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. CONCLUSIONS/INTERPRETATION: The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

A standardized protocol to achieve normoglycaemia during labour and delivery in women with type 1 diabetes.

AIM: To evaluate a standardized protocol for maintaining near-normoglycaemia during labour and delivery in women with type 1 diabetes. METHODS: Over a nine-year period (1997-2005), 229 pregnancies in 174 women with type 1 diabetes were delivered at one centre. The same regimen was used for the induction of labour (group 1) and in women admitted in spontaneous labour (group 2): 10% dextrose (80ml/h) intravenous was given along with short-acting insulin, starting at 1IU/h intravenous via an infusion pump. Capillary blood glucose (CBG) was determined hourly, and the insulin infusion rate was modified accordingly. RESULTS: Labour was induced in 85 cases (37%) and spontaneous in 23 cases (10%), and an elective C-section was performed in 121 cases (53%). Maternal glycaemia during labour was 6.1+/-1.6 (range: 3.9-9.2)mmol/l in group 1, and 6.9+/-2.0 (range: 4.7-12.0)mmol/l in group 2. Maternal glycaemia at delivery was 5.8+/-1.5 (range: 3.4-9.4) and 6.3+/-1.9 (range: 4.1-11.4)mmol/l in groups 1 and 2, respectively. Women who underwent an elective C-section were not included in the standardized protocol and had higher glycaemia at delivery 7.1+/-2.0 (range: 2.7-13.5)mmol/l. Neonatal hypoglycaemia occurred in 30 infants (13%), and was only associated with preterm delivery. CONCLUSION: Using a standardized simple protocol during labour, maternal glycaemia was maintained within a near-normal range in 80-85% of cases.

The Ala45Thr polymorphism of NEUROD1 is associated with type 1 diabetes in Brazilian women.

BACKGROUND: NEUROD1 encodes a transcription factor expressed in the endocrine pancreas, and involved in beta-cell development, function and mechanisms of apoptosis. In this study, we investigated the association of a frequent polymorphism in exon 2 of NEUROD1 (G > A; Ala45Thr) with Type 1 diabetes in Brazilian subjects. METHODS: A population/association study comprising 246 unrelated Type 1 diabetic and 275 nondiabetic white Brazilian subjects. The Ala45Thr variant was genotyped by a PCR-RFLP method. RESULTS: The frequency of the Thr allele was significantly higher in patients with Type 1 diabetes than in controls (42.3% vs 35.3%, P=0.02). Stratification by gender showed that homozygosity for the Thr allele was associated with Type 1 diabetes in women with odds ratio of 3.66 (95% C.I. 1.43-10.11, P=0.009) as compared to homozygosity for the Ala allele. This effect was not observed in men. CONCLUSIONS: We found a gender-specific association of the Ala45Thr variant of NEUROD1 with Type 1 diabetes in Brazilian women. Our results suggest that gender as well as ethnicity might modulate the association of NEUROD1 with Type 1 diabetes.

Vitamin D endocrine system and the genetic susceptibility to diabetes, obesity and vascular disease. A review of evidence.

The Vitamin D endocrine system regulates multiple aspects of calcium metabolism and cellular differentiation and replication in the immune system, endocrine pancreas, liver, skeletal muscles and adipocytes. It plays an important role in glucose homeostasis, notably, in the mechanism of insulin release. Actions of vitamin D are mediated by the binding of 1, 25-(OH)2D3 to a specific cytosolic/nuclear vitamin D receptor (VDR), a member of the steroid/thyroid hormone receptor superfamily. Several frequent polymorphisms are found in the VDR gene and were reported to be associated with a variety of physiological and pathological phenotypes in many populations. In this paper, we will review the evidences suggesting associations of allelic variations in the VDR gene and phenotypes related to body weight, glucose homeostasis, diabetes and its vascular complications.

Cutaneous manifestations of familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy is an autosomal dominant amyloidosis, characterized by the systemic deposition of amyloid with a particular involvement of the peripheral nerves. The disease generally manifests as a severe sensory, motor and autonomic neuropathy. Cardiomyopathy, nephropathy, vitreous opacities and carpal tunnel syndrome may occur in a variable association with the neuropathy. Trophic dermatological lesions are frequent in the more advanced stages of the disease. We examined the skin of 142 patients. The cutaneous manifestations more frequently observed were: xerosis (81.6%), seborrheic dermatitis (21.8%), traumatic and burn lesions (19.7%), acne (18.3%), neurotrophic ulcers (14%) and onychomycosis (10.5%). Among the hepatic transplanted patients (31%), seborrheic dermatitis and acne were the most frequent diagnoses.

The Gly482Ser polymorphism in the peroxisome proliferator-activated receptor-gamma coactivator-1 gene is associated with hypertension in type 2 diabetic men.

AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1) acts as a cofactor for several nuclear hormone receptors in many tissues and organs implicated in blood pressure regulation. Here, we assessed the association between the Gly482Ser variant of PPARGC1 and the arterial hypertension frequently found in subjects with type 2 diabetes. METHODS: We studied a group of 479 men and 253 women with type 2 diabetes. Arterial hypertension was present in 70% of the men and in 73% of the women. Genotypes were examined by PCR restriction fragment length polymorphism. A logistic regression analysis was performed to assess the covariables associated with arterial hypertension. RESULTS: There was an association between Ser allele homozygosis and arterial hypertension in type 2 diabetic men (odds ratio of 2.52 vs Gly allele homozygosis; 95% CI: 1.32-5.00; p=0.0064), but not in women. The prevalence of arterial hypertension in type 2 diabetic men was 77% vs 73% vs 67% for Ser-Ser, Gly-Ser and Gly-Gly carriers respectively (p=0.021). Age, BMI, the use of insulin, and triglyceride and creatinine levels were also independently associated with arterial hypertension in this cohort. CONCLUSIONS/INTERPRETATION: We have observed a sex-specific association between the PPARGC-1 gene Gly482Ser polymorphism and arterial hypertension in type 2 diabetic men. Further studies are needed to investigate the genetic, biochemical and pathophysiological basis of this allelic association.

Heterogeneidad de MODY y conducta clínica. ¿Diferentes genes como guía de distintos enfoques? / Clinical heterogeneity and clinical management of MODY. Different genes guiding different approaches?

Maturity onset diabetes of the young (MODY) es una forma familiar de diabetes no cetósica que usualmente aparece en niños, adolescentes o adultos jóvenes a consecuencia de defectos de la secreción insulínica que se heredan en forma de rasgo autosómico dominante. MODY no constituye una entidad nosológica única, sino que presenta heterogeneidad genética, metabólica y clínica. Las mutaciones en 6 genes ocasionan la mayoría de los casos de MODY. La presentación clínica de los diferentes subtipos de MODY difiere en diversos aspectos, especialmente en cuanto a la gravedad y curso natural del defecto de secreción insulínica y la consiguiente hiperglucemia, así como al riesgo de complicaciones microvasculares de la diabetes. Además, el espectro clínico de MODY es más amplio que el descrito inicialmente y podría incluir la afectación multiorgánica, además de la diabetes. En esta revisión debatimos la heterogeneidad y genética de MODY y las consecuencias sobre el tratamiento de la diabetes (AU)

MODY is a familial form of non-ketotic diabetes that usually develops in childhood, adolescence or young adulthood as a consequence of insulin-secretion defects inherited as an autosomal dominant trait. MODY is not a single entity and presents genetic, metabolic and clinical heterogeneity. Most cases of MODY are caused by mutations in six genes. The clinical presentation of the different MODY subtypes differs in several respects, notably in the severity and natural course of the insulin secretion defect and associated hyperglycemia, and in the risk of microvascular complications of diabetes. Moreover, the clinical spectrum of MODY is wider than initially described and might include multiorgan involvement in addition to diabetes. In this review we discuss the phenotypic heterogeneity associated with the genetic heterogeneity of MODY and the implications for the treatment of diabetes (AU)

[MODY in clinical practice. When and why to consider it?]. / Le diabète MODY en pratique. Quand y penser? Pourquoi y penser?

It is important to consider in clinical practice the diagnosis of MODY and to characterise the MODY sub-type. Indeed, evolution, clinical consequences and treatment of these forms of diabetes will be different according to the genetic origin of MODY. The main characteristics and consequences in clinical practice of these genetic abnormalities are briefly described, with a particular emphasis on the two most frequent sub-types, MODY-2 and MODY-3, caused by mutations of the enzyme glucokinase and of the transcription factor hepatocyte nuclear factor-1 alpha (HNF-1a) respectively.

Allelic variation in exon 18 of the sulfonylurea receptor 1 (SUR1) gene, insulin secretion and insulin sensitivity in nondiabetic relatives of type 2 diabetic subjects.

BACKGROUND: We have previously observed associations of the T-allele of the exon 18 variant (ACC --> ACT; Thr759Thr) of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus (T2DM). Here we assess beta-cell function and insulin sensitivity in carriers of different genotypes at this locus. METHODS: Pre-hepatic insulin secretion rates (ISR) derived by deconvolution of circulating C-peptide levels, and glucose clearance were assessed during graded infusions of intravenous glucose in CC-homozygous (n=6) and CT-heterozygous (n=6) nondiabetic relatives of CT-heterozygous type 2 diabetic subjects. RESULTS: Average ISR over the duration of the study, adjusted for sex, age, BMI and prevailing glucose levels, were lower in CT-heterozygous subjects as compared with CC-homozygous subjects (3.91 +/- 0.40 vs. 4.84 +/- 0.28 pmol/kg x min(-1); p=0.048). The correlation curves relating ISR to glucose levels were significantly different in the two groups (analyses of covariance p=0.029). Glucose clearance was similar in both groups. CONCLUSIONS: Insulin secretion rates, but not insulin sensitivity, assessed during graded infusion of glucose were mildly decreased in nondiabetic relatives of type 2 diabetic subjects, who carry the at risk T-allele of exon 18 variant of the SUR1 gene. These results suggest that the at-risk allele might have a small effect on pancreatic B-cell function and contribute to the development of T2DM in these families.

Sulfonylurea receptor -1 (SUR1): genetic and metabolic evidences for a role in the susceptibility to type 2 diabetes mellitus.

The pancreatic B-cell ATP-sensitive potassium channel (K(ATP)) is composed of two distinct subunits, an inwardly rectifying ion channel forming the pore (Kir6.2), and a regulatory subunit, namely the sulfonylurea receptor-1 (SUR1), which binds this widely used class of insulin-secreting drugs. Mutations in the genes encoding Kir6.2 and SUR1 may result in familial persistent hyperinsulinemic hypoglycaemia of infancy, demonstrating their role in the regulation of insulin secretion. Studies in various populations with different ethnic background provided evidence that various alleles of single nucleotide polymorphisms (SNPs) in the SUR1 gene, and to a less extent in the Kir6.2 gene, confer a significantly increased risk for the development of type 2 diabetes mellitus (T2DM). Allelic variations of these SNPs were shown to modulate insulin secretion and insulin sensitivity in vivo, thus providing a pathophysiological background to explain their contribution to the genetic susceptibility to T2DM. The aim of this review is to summarise and discuss the significant results of recent literature on the implication of K(ATP), and particularly of SUR1, in the genetic and pathopysiological mechanisms of T2DM.

Acral necrosis by Stenotrophomonas maltophilia.

BACKGROUND: Stenotrophomonas maltophilia (SM) has been considered a nosocomial pathogen. Nevertheless, community acquired infection may occur more frequently than usually recognized. CASE: We describe distal necrosis of the fingers by SM in a farmer, contracted in the community and successfully treated with a combination of cotrimoxazole and ciprofloxacin. The patient was diagnosed with chronic lymphocytic leukaemia 6 months later. CONCLUSIONS: This unusual presentation shows that infection with SM should be included in the differential diagnosis of the skin and soft tissue infection, even in apparently healthy patients.

Glucose-induced insulin hypersecretion in lipid-infused healthy subjects is associated with a decrease in plasma norepinephrine concentration and urinary excretion.

We investigated the effect of a 48 h triglyceride infusion on the subsequent insulin secretion in response to glucose in healthy men. We measured the variations in plasma concentration and urinary excretion of catecholamines as an indirect estimation of sympathetic tone. For 48 h, 20 volunteers received a triglyceride/heparin or a saline solution, separated by a 1-month interval. At time 48 h, insulin secretion in response to glucose was investigated by a single iv glucose injection (0.5 g/kg(-1)) followed by an hyperglycemic clamp (10 mg.kg(-1).min(-1), during 50 min). The triglyceride infusion resulted in a 3-fold elevation in plasma free fatty acids and an increase in insulin and C-peptide plasma concentrations (1.5- and 2.5-fold, respectively, P < 0.05), compared with saline. At time 48 h of lipid infusion, plasma norepinephrine (NE) concentration and urinary excretion levels were lowered compared with saline (plasma NE: 0.65 +/- 0.08 vs. 0.42 +/- 0.06 ng/ml, P < 0.05; urinary excretion: 800 +/- 70 vs. 620 +/- 25 nmol/24 h, P < 0.05). In response to glucose loading, insulin and C-peptide plasma concentrations were higher in lipid compared with saline infusion (plasma insulin: 600 +/- 98 vs. 310 +/- 45 pM, P < 0.05; plasma C-peptide 3.5 +/- 0.2 vs. 1.7 +/- 0.2 nM, P < 0.05). In conclusion, in healthy subjects, a 48-h lipid infusion induces basal hyperinsulinemia and exaggerated insulin secretion in response to glucose which may be partly related to a decrease in sympathetic tone.