Type 2 diabetes is both a phenotypically and geneotypically heterogeneous disease. It is caused by defective insulin secretion and action. Protein tyrosine phosphatases (PTPases) play important roles in insulin cascade signal transduction and have been suggested to be related to insulin resistance (1,2). PTP-1B, a member of the PTP family, is expressed widely in many tissues, acting as a negative regulator in the insulin receptor signal transduction pathway (3-5). The PTP-1B gene is located on the long arm of human chromosome 20, in the region of q13.1-q13.2, which has been linked to quantitative trait loci of obesity and insulin (6,7). A recent study by Echwald S.M. et al. (8) demonstrated that a Pro387Leu variation of the PTP-1B gene, which resulted in the impairment of the serine phosphorylation of the PTP-1B peptide (in vitro experiment), was associated with type 2 diabetes in a Danish Caucasian population with a genotype relative risk of 3.7 (CI 1.26～10.93, P=0.02). Since studies involving the association between the genetic variations and type 2 diabetes are often controversial and inconsistent in different ethnic populations, we tested the association between the Pro387Leu variation of PTP-1B gene with type 2 diabetes in a Chinese Han population for the first time. The Pro387Leu variation of PTP-1B gene was detected usingPCRand restriction ragment–length polymorphism in 589 subjects chosen from the Han population living in southern China, including 329 type 2 diabetic patients (men/women 143/186, age 59.4±9.9 years, BMI 23.9±3.5kg/m2) and 238 control subjects (men/women 100/138, age 57.5±8.3 years, BMI 23.8±3.1kg/m2). The control subjects underwent a 75-g oral glucose tolerance test and were diagnosed with normal glucose tolerance (NGT) in accordance with the 1997 American Diabetes Association criteria. The study was approved by the ethnics committee of our institution. All the subjects gave informed consent. In our study, only two subjects heterozygous for the mutation were found in the NGT control group, with genotype and allele frequencies of 0.008 and 0.004, respectively. We found another two heterozygotes in the diabetic patient group; the genotype and allele frequencies were 0.006 and 0.003, respectively. The differences did not reach statistical significance between groups (P= 0.05 for both). The distribution was consistent with Hardy-Weinberg equilibrium. We then examined the impacts of the mutation on metabolic and anthropometric parameters in both groups. Among NGT control subjects, there were no significant differences in age, fasting plasma glucose (FPG), or lipid profile between the two subgroups with or without the Leu387 mutation (P=0.05), while BMI was significantly higher in subjects with the Leu387 allele (23.74±3.05 vs. 28.55±2.19 kg/m2, P=0.027). In the diabetic patient group, no differences were observed in age, BMI, FPG, HbA1c, Cpeptide, or lipid profile (P=0.05). Since the mutation rate was quite low in the examined Chinese Han population and at the same time there were 31 subjects with a BMI＞27kg/m2 in the subgroup without the Leu387 mutation, the difference found in BMI between the mutation carriers and noncarriers in the control group was likely attributed to individual variance rather than the true difference caused by the presence of the mutation. In conclusion, our data indicated that the mutation of Pro387Leu in PTP-1B gene was present in the Chinese Han population examined, but this variation wa

OBJECTIVE—To investigate whether long-term optimal glycemic control can be achieved without medication by transient continuous subcutaneous insulin infusion (CSII) and the possible mechanisms responsible for this remission. RESEARCH DESIGN AND METHODS—Newly diagnosed type 2 diabetic patients (n=138, fasting glucose＞11.1mmol/l) were hospitalized and treated with CSII for 2 weeks. Intravenous glucose tolerance tests (IVGTTs) were performed, and blood glucose, HbA1c, lipid profiles, proinsulin, insulin, and C-peptide were measured before and after CSII. Patients were followed longitudinally on diet alone after withdrawal of insulin. RESULTS-Optimal glycemic control was achieved within 6.3±3.9 days by CSII in 126 patients. The remission rates (percentages maintaining near euglycemia) at the third, sixth, twelfth, and twenty-fourth month were 72.6, 67.0, 47.1, and 42.3%, respectively. Patients who maintained glycemic control 12 months (remission group) had greater recovery of β-cell function than those who did not (nonremission group) when assessed immediately after CSII. Homeostasis model assessment of β-cell function (HOMA-B) and the area under the curve (AUC) of insulin during IVGTT were higher in the remission group (145.4±89.6 vs. 78.5±68.5, P=0.002, and 1,423.4±523.2 vs. 1,159.5±476.8 pmol-l•min-1, P=0.044). Change in acute insulin response was also greater in the remission group than that in the nonremission group (621.8±430.4 vs. 387.3±428.8pmol-l•min-1, P=0.033). CONCLUSIONS—Short-term intensive insulin therapy can induce long-term glycemic control in newly diagnosed type 2 diabetic patients with severe hyperglycemia. The improvement of β-cell function, especially the restoration of first-phase insulin secretion, could be responsible for the remission.

To examine whether defective muscle glycogen synthase (GYS1) expression is associated with impaired glycogen synthesis in type 2 diabetes and whether the defect is inherited or acquired, we measured GYS1 gene expression and enzyme activity in muscle biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and in 12 matched control subjects. The effect of insulin on GYS1 fractional activity, when expressed as the increment over the basal values, was significantly impaired in diabetic (15.7±3.3%; P＜0.01), but not in nondiabetic (23.7±1.8%; P =NS) twins compared with that in control subjects (28.1±2.3%). Insulin increased GYS1 messenger ribonucleic acid (mRNA) expression in control subjects (from 0.14±0.02 to 1.74±0.10 relative units; P, 0.01) and in nondiabetic (from 0.24±0.05 to 1.81±0.16 relative units; P＜0.01) and diabetic (from 0.20±0.07 to 1.08±0.14 relative units; P＜0.01) twins. The effect of insulin on GYS1 expression was, however, significantly reduced in the diabetic (P, 0.003), but not in the nondiabetic, twins compared with that in control subjects. The postclamp GYS1 mRNA levels correlated strongly with the hemoglobin A1c levels (r=-0.61; P＜0.001). Despite the decrease in postclamp GYS1 mRNA levels, the GYS1 protein levels were not decreased in the diabetic twins compared with those in the control subjects (2.10±0.46 vs. 2.10±0.34 relative units; P 5 NS). We conclude that 1) insulin stimulates GYS1 mRNA expression; and 2) impaired stimulation of GYS1 gene expression by insulin in patients with type 2 diabetes is acquired and most likely is secondary to chronic hyperglycemia.

115 Finnish and Swedish patients with early-onset (≤40 years) diabetes using the single strand conformation polymorphism (SSCP) technique and direct sequencing. Allele frequencies were compared with 118 patients with onset of diabetes Type II (non-insulin-dependent) diabetes mellitus after the age of 40 and 92 non±diabetic control subjects without a family history of diabetes. Results. In total 52 sequence variants were found in the HNF-1a, HNF-4a and glucokinase genes, 12 of which were considered as MODY mutations. Three families had the A3243G mutation in the mitochondrial tRNALeu gene, which resulted in an overall prevalence of these mutations of 13%. Conclusion/interpretation. Among 115 Scandinavian families, mutations in the HNF-1a gene represented the most common cause of familial early-onset (≤40 years) diabetes: MODY3 (5.2%) more than MODY2 (3.5%) more than MIDD (2.6%) more than MODY1 (1.7%). [Diabetologia (1999) 42: 1131-1137]