with modeRate Renal insufficiency Summary : Numerous patients with type 2 diabetes have renal impairment, especially in the elderly population. Metformin, the first choice oral glucose-lowering agent, is classically contraindicated in case of chronic kidney disease of stages 3-5 (creatinine clearance < 60 ml/min/1.73 m²), because of a risk of accumulation of the biguanide that may lead to lactic acidosis. Hence numerous patients with some degree of renal impairment are being treated with metformin in clinical practice, apparently without any harm. In contrast, several observational studies have shown that they may clinically benefit from this therapy, including with a significant reduction of all-cause mortality when compared to patients not receiving metformin. Thus, an increasing number of physicians plea for revisiting the official criteria of contraindication to the use of metformin in case of renal insufficiency. The present paper discusses this controversy and insists upon the mandatory cautions to be taken when using metformin in a diabetic patient with moderate (stage 3) chronic kidney disease (metformin being contraindicated in case of severe renal impairment - stages 4-5).

Les anomalies du metabolisme du glucose sont frequentes chez le sujet presentant une obesite severe. Meme lorsque la tolerance au glucose reste normale dans le decours d'une hyperglycemie provoquee par voie orale (HGPO), des anomalies de l'action (insulino-resistance), du metabolisme (diminution de la clairance) et de la secretion (hypersecretion precoce et tardive) de l'insuline sont objectivees par une hyperglycemie provoquee par voie intraveineuse (HGPIV) chez les sujets obeses. Par ailleurs, une diminution de la tolerance au glucose, voire un diabete, est observee dans 20 % des cas environ et ce, davantage chez les hommes que chez les femmes. Les troubles du metabolisme du glucose et ses corollaires sur les anomalies de l'insuline sont reversibles, ainsi qu'en temoigne la normalisation de la secretion, du metabolisme et de l'action de l'insuline au cours d'une HGPIV chez des femmes ayant recupere leur poids ideal, 14 ± 2 mois apres une gastroplastie. En presence d'un diabete avere, l'amelioration du controle glycemique peut egalement etre spectaculaire apres amaigrissement et permet une reduction substantielle du traitement pharmacologique, par antidiabetiques oraux ou par insuline. En conclusion, l'obesite joue un role determinant dans l'histoire naturelle du diabete non insulino-dependant et le traitement efficace de l'exces de poids represente un objectif fondamental dans la prevention et le traitement de ce type de diabete.

SUMMARY Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5′ region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients < 40 years old we investigated the possible interactions of a CTLA-4 gene A-to-G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA-DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients, G-allele-containing CTLA-4 genotypes (relative risk (RR) = 1.5; 95% confidence interval (CI) = 1.2–2.0; P < 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA-DR3 or DR4 alleles; HLA-DQA1*0301-DQB1*0302 and/or DQA1*0501-DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA-2-Ab, GAD65-Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti-thyroid peroxidase, anti-thyroid-stimulating hormone (TSH) receptor, anti-parietal cell, anti-intrinsic factor) were determined, but association between CTLA-4 risk genotypes and markers of polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA- or INS-linked risk. In conclusion, the presence of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.

In 157 new onset IDDM (104 men, 53 women, ages 10-39 yr) anti-thyroid peroxidase anti-bodies (anti-TPO) were assayed with a specific immunological test. Values greater than 100 U ml(-1) were considered positive. Seventeen per cent of the patients were positive (32% of the women versus 10% of the men, p < 0.001). Eighty-five per cent of the anti-TPO+ patients have a positive titre of islet-cell antibodies (ICA greater than or equal to 12 JDFU) versus 64% of the anti-TPO-patients (p < 0.05). When patients were subdivided in a young (10-25 yr) and an older age group (26-39 yr) this association was also true for ICA greater than or equal to 50 JDFU and valid for insulin autoantibodies (IAA) at low (greater than or equal to 0.7%) and high risk (greater than or equal to 1.5%) (p < 0.005) in the second group. The median of the TSH concentration was not different between anti-TPO+ and anti-TPO- when the group is considered as a whole. In the anti-TPO+ men (26-39 yr) TSH was however significantly greater (1.55 mu U ml(-1), range 0.74-8.5 versus 1.4 mu U ml(-1), range 0.21-3.5, p < 0.0001) when compared to the anti-TPO-men of the same age group. The haplotype HLA DQA1*0301-DQB1*0302 was more frequent in the anti-TPO+ (39%) than in the anti-TPO- (23%) patients (p < 0.02) for the age group 26-39 yr but not for the age group 10-25 yr. The other diabetes susceptibility haplotype DQA1*0501-DQB1*0201 was less frequent in anti-TPO+ patients. In conclusion we suggest that thyroid auto-immunity must be part of the initial screening of IDDM especially when patients are older at clinical onset of the disease.

Pancreatic amylase and lipase activities were measured in sera of 307 Caucasian insulin-dependent diabetes mellitus patients (IDDM) at clinical onset, 303 nondiabetic siblings of registered patients, and 207 control subjects under age 40 years. In all subject groups lipasemia and pancreatic (but not salivary) amylasemia increased with age and were significantly correlated. Using age-dependent reference ranges, reduced pancreatic enzyme levels were measured in 18% of patients, 6% of siblings, and only 2% of control subjects (p < 0.001). Increased lipase levels were noted in 10% of patients and in only 3% of siblings and 2% of control subjects (p < 0.001). Using both univariate and multivariate statistical analysis, elevated lipase activities at clinical onset were associated with higher titers of autoantibodies against islet cell cytoplasmic antigens and glucagon, but not against insulin or the 65-kDa isoform of glutamic acid decarboxylase (GAD65-Ab), or with markers of genetic predisposition or metabolic dysregulation. These findings indicate the presence of modest, but statistically significant, variations in circulating pancreatic enzyme levels in 28% of IDDM patients at clinical onset (p < 0.001 vs. 5% in control subjects). Increased lipase levels may express a form or a stage of the disease with exocrine cell damage; their association with higher titers of islet cell and glucagon autoantibodies is not yet explained. Lower lipase and isoamylase levels are thought to result from the reduced acinar cell function in the vicinity of insulin-depleted islets. It must be tested whether pancreatic enzyme activities in serum can also be altered during the preclinical stage and can thus be considered as an additional marker for the disease process in the pancreas.

Patients with adult-onset Type 1 (insulin-dependent) diabetes mellitus (IDDM) are more difficult to identify than young patients, as their clinical onset is often less acute with a questionable state of insulin dependency. Classification may be facilitated by the detection of autoantibodies that are associated with IDDM. The prevalence of islet cell autoantibodies (ICA) and insulin autoantibodies (IAA) is, however, markedly lower in adult than in young patients. The present study assesses the usefulness of antibodies against glutamate decarboxylase (GAD), as a complementary marker. Sera from 312 recent-onset IDDM patients under age 40 and 163 age-matched controls were assayed for IAA, ICA, and antibodies against recombinant GAD65 (M(r) 65,000) or GAD67 (M(r) 67,000). IAA or ICA occurred in over 90% of patients diagnosed under age 20 but only in 65% of patients between age 20 and 40. Determination of GAD65-Ab did not increase the percent antibody positive patients under age 10, but did so at older ages: from 92-98% in the 10-19 years age group, and from 65-85% in the 20-39 years age group. The determination of GAD67-Ab did not add to the information provided by the GAD65-Ab assay. Our results indicate that, alone or in combination with ICA, the GAD65-Ab assay identified more patients with an IDDM marker in the age group 20-39 years than in the group under age 20.

In recent-onset type 1 (insulin-dependent) diabetes mellitus (IDDM), insulin autoantibodies (IAA) and islet cell antibodies (ICA) occur preferentially in young (< 10 yr) patients with the HLA DQA1*0301-DQB1*0302 risk haplotype. We investigated whether this association also exists in siblings of IDDM patients. In our group of 310 siblings, aged 0-39 yr, 6% were positive for IAA, 7% for ICA 12 Juvenile Diabetes Foundation units (JDFU) or more, 5% for ICA 20 JDFU or more, and 2% for high titer ICA (> or = 80 JDFU). The occurrence of IAA and ICA (> or = 20 JDFU) was significantly associated, with a preferential relationship to the HLA DQA1*0301-DQB1*0302 susceptibility haplotype. In the present group of siblings, IAA and DQA1*0301-DQB1*0302 were significantly associated under age 10 yr (26% positivity for IAA vs. 4% in relatives without this haplotype). In this age group, IAA were more prevalent than (high titer) ICA (6%) in the presence of the haplotype. The association between (high titer) ICA and DQA1*0301-DQB1*0302 was not restricted to subjects under age 10 yr. High titer ICA (n = 5) occurred exclusively in homozygotes for the latter haplotype and in carriers of the heterozygous DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 high risk genotype, mostly under age 20 yr (four of five). The preferential occurrence of IAA in DQA1*0301-DQB1*0302-positive siblings under age 10 yr was caused by their high prevalence (47%) in subjects with the heterozygous high risk genotype in this age group. As in patients at onset, IAA and high titer ICA are preferentially associated with the DQA1*0301-DQB1*0302 haplotype in siblings of IDDM patients, but, unlike at onset, these associations are observed with specific genotypes only and are more pronounced in subjects under age 10 yr for IAA only. Longitudinal analysis in first degree relatives and other normal controls carrying the DQA1*0301-DQB1*0302 haplotype should assess the hypothesis that IAA qualify as earlier predictive markers for IDDM than high titer ICA.