Icariin promotes mouse hair follicle growth by increasing insulin-like growth factor 1 expression in dermal papillary cells.

BACKGROUND: Icariin is a major flavonoid isolated from Epimedium spp. leaves (Epimedium Herba), and has multiple pharmacological functions, including anti-angiogenesis, anti-oxidant, anti-inflammatory and immunoprotective effects. AIM: To investigate whether icariin can stimulate growth of hair follicles in mice and the underlying mechanism. METHODS: In vitro, the effect of icariin on hair growth was assessed by using a vibrissae hair follicle (VHF) organ-culture model. The proliferation of hair matrix keratinocytes and the expression of insulin-like growth factor (IGF)-1 in follicles were examined by double immunostaining for 5-bromo-2'-deoxyuridine and IGF-1, in the presence or absence of icariin. Dermal papilla cells (DPCs) were cultured and IGF-1 level was measured by reverse transcription-PCR and ELISA after icariin treatment. In vivo, the effect of icariin on hair growth was examined by gavage feeding of icariin to mice whose backs had been depilated, and the conversion of telogen to anagen hair was observed. RESULTS: Treatment with icariin promoted hair shaft elongation, prolonged the hair cycle growth phase (anagen) in cultured VHFs, and accelerated transition of hair cycle from telogen to anagen phase in the dorsal skin of mice. There was significant proliferation of matrix keratinocytes and an increased level of IGF-1 in cultured VHFs. Moreover, icariin treatment upregulated IGF-1 mRNA expression in DPCs and increased IGF-1 protein content in the conditioned medium of DPCs. CONCLUSIONS: These results suggest that icariin can promote mouse hair follicle growth via stimulation of IGF-1 expression in DPCs.

Interaction of alloxan and anomers of D-glucose on glucose-induced insulin secretion and biosynthesis in vitro.

The direct effects of alloxan on glucose-induced insulin secretion and biosynthesis and the interaction of alloxan and D-glucose anomers were studied in vitro by use of isolated islets from rat pancreas. Islets were pretreated by incubation for five minutes in media containing alloxan (0.2 mg./ml.) alone or alloxan with either the alpha or beta anomer of D-glucose (3 mg./ml.). After washing, batches of five islets were incubated in the medium supplemented with glucose (1.8 mg./ml.) for 60 minutes to observe insulin secretion and for 90 minutes to observe insulin biosynthesis. Prior exposure to alloxan alone produced marked inhibition of subsequent glucose-induced insulin secretion and biosynthesis. A significantly greater protection against these inhibitory effects of alloxan was observed by using the alpha anomer of D-glucose than the beta anomer. The anomeric preference of D-glucose for protecting islet cells from the inhibitory effect of alloxan on glucose-induced insulin secretion and biosynthesis was similar to that for triggering insulin secretion. Possible mechanisms of the inhibitory effect of alloxan and the protective effect of D-glucose anomers in connection with those of other sugars are discussed. It is suggested that a glucoreceptor, stereospecific to the alpha anomer of D-glucose, may exist for both insulin secretion and biosynthesis.

Link between hypertension and diabetes mellitus epidemiological study of Chinese adults in Taiwan.

OBJECTIVE: To elucidate the relationship between hypertension and non-insulin-dependent diabetes. RESEARCH DESIGN AND METHODS: The study consisted of a random sample of adults aged greater than or equal to 40 yr from the Ta-An district of Taipei City and 5 of 12 villages of Taiwan province, which had established primary health-care centers since 1984. A total of 11,478 subjects were recruited into the survey with a response rate of 65.3 and 72%, respectively. Blood glucose and blood pressure levels were measured, and a structured questionnaire was given to each participant. Those identified as having diabetes received further blood tests for lipids and creatinine and were evaluated for vascular complications. RESULTS: The age- and sex-adjusted prevalence of hypertension among diabetic subjects was twice that of nondiabetic subjects (30.6 vs. 16.4%, P less than 0.0005). Hypertensive subjects had a higher prevalence of diabetes than normotensive subjects (10.2 vs. 4.9%, P less than 0.0005). Among hypertensive subjects, the prevalence of diabetes was 12.7% for those taking antihypertensive drugs and 9.1% for those not taking any drug (P less than 0.05). The prevalence of diabetes significantly increased as mean arterial pressure rose, whether the subjects were stratified by various factors. Multiple regression analysis, including sex, age, body mass index, and other risk factors as independent variables, also showed a significant association between diabetes and hypertension. CONCLUSIONS: The univariate and multivariate analyses revealed that there seemed to be a tight link between hypertension and non-insulin-dependent diabetes. Family history of diabetes, diabetes duration, diabetes regimen, control of blood glucose, and the presence of nephropathy, as attested by proteinuria, did not contribute to the risk of hypertension. Further studies are necessary to determine whether these two conditions are causally related.

Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 heterozygotes and IDDM in Taiwanese families.

OBJECTIVE: To study the human leukocyte antigen (HLA)-DQ heterodimers in the susceptible DR haplotypes for patients with insulin-dependent diabetes mellitus (IDDM) in Taiwan. RESEARCH DESIGN AND METHODS: Extended class II HLA haplotypes were studied in 57 unrelated IDDM patients, 31 simplex IDDM families, and 105 unrelated control subjects recruited from the same area in Taiwan. Class II HLA genotyping was based on PCR-SSO DNA typing techniques. Extended class II HLA haplotypes were deduced unequivocally by the Taiwanese pedigree studies. RESULTS: DR3/DR3, DR3/DR4, and DR3/DR9 genotypes were strongly associated with IDDM susceptibility in this population. In addition to the reported DR3/DR4 in Caucasians, the heterozygotic effect of DR3/DR9 for IDDM was remarkable in the Taiwanese population. Extended HLA haplotypes studies revealed that DRB1*0301/DQA1*0501/DQB1*0201, DRB1*0405/DQA1*0301/DQB1*0302, and DRB1*0405/DQA1*0301/DQB1*0401 were the susceptible haplotypes in this population. There were several hypothetical ways to produce susceptible HLA-DQ heterodimers to explain the susceptibility carried by DR3/DR4 and DR3/DR9 genotypes. Among all DR4 subtypes, only DRB1*0405 was associated with the increased risk of IDDM. CONCLUSIONS: These data strongly suggest that the HLA-DR-associated IDDM susceptibility is most likely explained by the formation of the susceptible DQ heterodimers encoded by the DQA1/DQB1 either in cis or in trans.

No association between the Gly971Arg variant of the insulin receptor substrate 1 gene and NIDDM in the Taiwanese population.

OBJECTIVE: To study the role of the Gly971Arg variant of the insulin receptor substrate 1 (IRS-1) gene in the development of NIDDM in the Chinese population living in Taiwan. RESEARCH DESIGN AND METHODS: A total of 82 unrelated normal control subjects, 89 subjects with NIDDM, and 23 multiplex families were recruited in Taiwan. All of them were Han Chinese. Pedigree members without a history of diabetes were studies by the standard 75-g oral glucose tolerance test. Detection of the Gly971Arg variant of the IRS-1 gene was performed by polymerase chain reaction and restriction fragment-length polymorphism analysis. RESULTS: The frequency of Gly971Arg variant of the IRS-1 gene in the normal population was 1.2% which was lower than frequencies reported in white populations. The prevalence of the Gly971Arg variant was not significantly increased in both the nonselected NIDDM population (1.1%) and the probands of the multiplex families (4.3%). More importantly, the Gly971Arg variant of the IRS-1 gene did not cosegregate with BMI and NIDDM in these families, CONCLUSIONS: The Gly971Arg variant of the IRS-1 gene is an infrequent normal allele among Taiwanese. This variant is neither associated nor cosegregated with NIDDM in the Taiwanese population and families. Gly971Arg of IRS-1 gene does not play an important role in the development of NIDDM in this population.

HLA-DQB1 codon 57 and IDDM in Chinese living in Taiwan.

OBJECTIVE: To study the human leukocyte antigen (HLA)-DQB1 genetic background in the Chinese population in Taiwan and its association with the low incidence of insulin-dependent diabetes mellitus (IDDM) in this population. RESEARCH DESIGN AND METHODS: Forty-eight IDDM patients and 59 nondiabetic unrelated control subjects were recruited from the population in Taiwan. HLA-DQB1 exon 2 was enzymatically amplified by polymerase chain reaction. HLA-DQB1 alleles were diagnosed by dot blotting and hybridization with 16 sequence-specific oligonucleotide probes. RESULTS: DQB1*0201 and DQB1*0302 alleles were more frequent and DQB1*0301 and DQB1*0601 were less frequent in Chinese with IDDM than in control subjects. Genotypes for homozygous non-aspartic acid residue (NA/NA) at position 57 were positively associated with IDDM at a relative risk of 4.34 (P < 0.001), and those for homozygous aspartic acid (A/A) were negatively associated with IDDM at a relative risk of 0.14 (P < 0.001). Among the NA/A heterozygotes, only DQB1*0201/DQB1*0303 was significantly increased in IDDM subjects. CONCLUSIONS: The amino acid residue at position 57 of HLA-DQ beta-chain is significantly associated with the development or prevention of IDDM in Chinese subjects living in Taiwan. Other genetic and environmental factors may also play important roles in pathogenesis of IDDM.

Insulin biosynthesis: the monoaminergic mechanisms and the specificity of "glucoreceptor".

Islets of Langerhans, isolated from the rat, did not synthesize insulin in the presence of L-glucose, fructose, galactose, 3-0-methyl glucose or sorbitol. A small amount of insulin was synthesized in the presence of glucosamine. Addition of caffeine to these compounds did not enhance the biosynthesis of insulin. It is suggested that the specificity of the membrane surface "glucoreceptor", if it exists, may be rather narrow, at least with respect to insulin biosynthesis. Serotonin, dopamine and isoproterenol did not inhibit or enhance insulin biosynthesis induced by glucose. Propranolol also failed to modify insulin synthesis in the absence or presence of isoproterenol. It is concluded that the monoaminergic mechanisms do not affect insulin biosynthesis in spite of their significant regulatory influence on insulin release. Methysergide, at the concentration reported to potentiate insulin release induced by glucose and tolbutamide in rabbit, strongly inhibited insulin biosynthesis.

Hypothalamic-pituitary-adrenal axis function in very low birth weight infants treated with dexamethasone.

The effect of dexamethasone therapy on hypothalamic-pituitary-adrenal axis function was prospectively investigated in very low birth weight infants with bronchopulmonary dysplasia. Ten infants (mean +/- SD birth weight 825 +/- 265 g, gestation 25.8 +/- 1.9 weeks, postnatal age 33.1 +/- 17.7 days) initially received intravenous dexamethasone, 0.5 mg/kg per day for 3 days, and then were weaned over a period of 45 +/- 19.0 days to a replacement dose, followed by a metyrapone test. Morning plasma cortisol and 11-deoxycortisol levels were measured before and after an oral metyrapone dose given at midnight. Five infants (group A: birth weight 876 +/- 313 g, gestation 26.2 +/- 1.3 weeks, age of entry 31.8 +/- 22.8 days) had normal metyrapone test results, and five infants (group B: 778 +/- 234 g, 25.4 +/- 2.5 weeks, 34.4 +/- 13.4 days) had suppressed test results. Group A infants, in comparison with group B infants, had higher basal cortisol plasma levels (14.52 +/- 12.53 and 3.00 +/- 1.38 micrograms/dL, P = .047), higher postmetyrapone 11-deoxycortisol plasma levels (3.11 +/- 3.93 and 0.55 +/- 0.51 micrograms/dL, P = .028), larger differences between basal and postmetyrapone cortisol levels (7.10 +/- 4.67 and 2.12 +/- 1.31 micrograms/dL, P = .047), and larger differences between basal and postmetyrapone 11-deoxycortisol levels (2.99 +/- 3.93 and 0.29 +/- 0.25 micrograms/dL, P = .009). The hypothalamic-pituitary-adrenal axis function in group B infants eventually returned to normal when they continued to receive low-dose dexamethasone therapy after a period of 36.8 +/- 16.6 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of insulin-dependent diabetes mellitus in Taiwan with HLA class II DQB1 and DRB1 alleles.

The allelic constitution at HLA class II DRB1, DQB1, DQA1, and DPB1 loci of IDDM patients from Taiwan was compared with that of ethnically matched nondiabetic individuals by PCR-based DNA typing. Of the three haplotypes found to be positively associated with IDDM in Taiwan, two (DRB1*0301-DQA1*0501-DQB1*0201 and DR4-DQA1*0301-DQB1*0302) appear to be identical to the susceptible haplotypes in Caucasian and black populations, whereas the third haplotype (DR4-DQA1*0301-DQB1*04) has been reported to be positively associated with IDDM only in the Japanese population. The three haplotypes, DRB1*1502-DQA1*0102-DQB1*0601 and DRB1*1201 (or 1202)-DQA1*0501-DQB1*0301 and DRB1*0803-DQA1*0103-DQB1*0601, were negatively associated with IDDM in Taiwan; a protective effect of the last haplotype has not been reported previously. Neither DQ beta non-Asp-57 nor DQA1*0301 alone appears sufficient to account for the HLA-associated susceptibility to IDDM in Taiwan. Also, the DQ alpha beta heterodimer encoded by the alleles DQA1*0301/DQB1*0201, DQA1*0301/DQB1*0302, or DQA1*0501/DQB1*0201 does not explain the susceptibility of a larger fraction of the IDDM patients than the residue at position 57 of the DQ beta chain or DQA1*0301. Finally, the DRB1 alleles appear to affect IDDM susceptibility, although for most haplotypes the effect of individual loci cannot be assessed due to the linkage disequilibrium between the DQ and the DR region.

Long-term arsenic exposure and incidence of non-insulin-dependent diabetes mellitus: a cohort study in arseniasis-hyperendemic villages in Taiwan.

Diabetes prevalence in arseniasis-hyperendemic villages in Taiwan has been reported to be significantly higher than in the general population. The aim of this cohort study was to further evaluate the association between ingested inorganic arsenic and the incidence of non-insulin-dependent diabetes mellitus in these villages. A total of 446 nondiabetic residents in these villages were followed biannually by oral glucose tolerance test. Diabetes is defined as a fasting plasma glucose level > or = 7.8 mmol/L and/or a 2-hr post-load glucose level > or = 11.1 mmol/L. During the follow-up period of 1499.5 person-years, 41 cases developed diabetes, showing an overall incidence of 27.4/1,000 person-years. The incidence of diabetes correlated with age, body mass index, and cumulative arsenic exposure. The multivariate-adjusted relative risks were 1.6, 2.3, and 2.1 for age > or = 55 versus < 55 years, a body mass index ¿Greater/Equal to] 25 versus < 25 kg/m(2), and a cumulative arsenic exposure > or = 17 versus < 17 mg/L-years, respectively. The incidence density ratios (95% confidence intervals) between the hyperendemic villages and the two nonendemic control townships were 3.6 (3.5-3.6), 2.3 (1.1-4.9), 4.3 (2.4-7.7), and 5.5 (2.2-13.5), respectively, for the age groups of 35-44, 45-54, 55-64, and 65-74 years. The findings are consistent with our previous cross-sectional observation that ingested inorganic arsenic is diabetogenic in human beings.

Isochromosome 11q in a case of acute myelomonocytic leukemia FAB type M4.

The clinical and cytogenetic findings in a 42-year-old female with acute myelomonocytic leukemia (AMMoL) were reported. At diagnosis, cytogenetic studies of bone marrow cells revealed the karyotype 45; XX, +8, -11, -17, -18, +i (11q). To our knowledge, this is the second case of AMMoL with i(11q) in the literature.

Signal transduction pathways for interleukin 4 and insulin in human hepatoma cells.

IRS-1 has been found to relay the signals from the receptors for insulin, insulin-like growth factor-1, growth hormone, and many cytokines for the downstream effects in the various cell types tested. For interleukin 4 signaling, most studies were performed on hematopoietic cells and cell lines transfected with rat liver IRS-1 cDNA. In a liver cell lineage, IRS-1 expression has been found to be increased in hepatoma cells and hepatocytes in regenerating liver. To elucidate the possible function and the signal transduction pathway for interleukin 4, in comparison with insulin, in liver cells, we used the Hep 3B hepatoma cell line as a model system. Following insulin and interleukin 4 stimulation, rapid tyrosyl phosphorylation of IRS-1 occurred. Interleukin 4, but not insulin, stimulated the tyrosine phosphorylation of JAK1 and, to a lesser extent, JAK2. In contrast to the other cell types, the association of IRS-1 and Grb2 through the SH2 of Grb2 was demonstrated after IL-4 and insulin stimulation of the Hep3B hepatoma cells. Both insulin and interleukin 4 stimulated tyrosine phosphorylation and the enzyme activity of Erk1 kinase. Our results indicate that interleukin 4 and insulin might modulate hepatic cell growth and differentiation through many different or common pathways for the activation of JAK kinases and the usage of IRS-1 as a docking protein. The binding of IRS-1 with Grb2 after IL-4 as well as insulin stimulation may lead to MAP kinase activation, probably through the Grb2/sos/p21ras pathway.

Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients with hypertension, non-insulin-dependent diabetes mellitus, and coronary heart disease in Taiwan.

An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been identified that determines most of the plasma ACE activity genetically. Association of the D allele with insulin sensitivity and of the D/D genotype with coronary heart disease (CHD) has been reported in various ethnic populations. To study the role of this genetic polymorphism in patients with hypertension, non-insulin-dependent diabetes mellitus (NIDDM), and NIDDM with CHD in a Taiwanese population, we used a polymerase chain reaction (PCR)-based genotyping technique with an insertion-specific primer for confirmation of the I allele. One hundred ninety-seven unrelated normal controls, 67 subjects with hypertension, 107 subjects with NIDDM, and 70 subjects with NIDDM and CHD were recruited for this study; all were Han Chinese. Subjects without a history of diabetes were studied by a standard 75-g oral glucose tolerance test. Hypertension was diagnosed according to the Fifth Joint National Committee criteria, and CHD was confirmed by a history of acute myocardial infarction and coronary angiographic intervention. The frequency of the I allele of the ACE gene in the normal population was 64.2%, which was higher than reported in white populations. The prevalence of the I allele of the ACE gene was not significantly increased in subjects with hypertension (73.1%), NIDDM (62.1%), and NIDDM with CHD (65%) compared with healthy controls. The I allele of the ACE gene did not correlate with demographic and metabolic variables. I/D polymorphism of the ACE gene is not a marker for hypertension, NIDDM, or CHD in this Taiwanese population.

A case of basophilic leukemia bearing simultaneous translocations t(8;21) and t(9;22).

We report a case of basophilic leukemia with simultaneous translocations of t(8;21) and t(9;22). The patient's clinical and hematologic findings were characteristic only of t(9;22) but not of t(8;21). This unusual cytogenetic phenomenon raises a challenge to the current concepts of primary chromosomal abnormalities in cancer.

The time for serum testosterone to reach castrate level after bilateral orchiectomy or oral estrogen in the management of metastatic prostatic cancer.

OBJECTIVE: To understand the time for serum testosterone to reach castrate level after bilateral orchiectomy or oral estrogen in the management of metastatic prostatic cancer. METHODS: A total of 20 consecutive patients with adenocarcinoma of the prostate with bony metastasis were enrolled in this study. Their mean age was 72.8 years old (range, 57 to 82 years). Pretreatment serum testosterone levels were obtained in all men. Thirteen men were treated with bilateral orchiectomy. Immediately after removal of testes, serial blood samplings for serum testosterone levels were drawn every fifteen minutes for the first two hours, then hourly for another sixteen hours. Seven men were treated with oral estrogen diethylstilbestrol (DES), 3 mg per day. Serum testosterone levels were checked on a weekly basis for two months, and then biweekly for another two months. RESULTS: Castration time of bilateral orchiectomy ranges from three to twelve hours (mean, 8.6 hours). The biological half-life of serum testosterone was from thirty to sixty minutes (mean, 45 minutes). Castration time of oral estrogen (DES) was from twenty-one to sixty days (mean, 38.3 days). CONCLUSIONS: Bilateral orchiectomy and oral estrogen were both effective ways of castration for patients with bony metastatic prostatic cancer. Bilateral orchiectomy provides a more rapid castration and is one hundred seven times faster than oral estrogen in reaching castrate level.

Quantitative sensory testing and risk factors of diabetic sensory neuropathy.

The goal of this study was to identify risk factors for diabetic peripheral sensory neuropathy in type 2 diabetes mellitus in a Chinese population. Peripheral sensory neuropathy was detected by quantitative sensory testing (5.07/10 g monofilament, neurometer and 128-Hz Riedel Seiffert graduated tuning fork). Those who had two or more abnormal quantitative sensory testings were defined as having diabetic sensory neuropathy. Of the 558 non-insulin dependent diabetes mellitits subjects, 62 (11.1%) had peripheral neuropathy. In 59 (10.6%) detection was by monofilament testing, 45 (8.1%) by graduated tuning fork, and 189 (33.9%) by neurometer. In a multivariate logistic regression model, age and insulin therapy were significantly associated with peripheral neuropathy. Age, serum triglyceride, height, and fasting plasma glucose were independently associated with large fiber neuropathy. Our results confirm the previously identified multiple risk factors of diabetic neuropathy. Different quantitative sensory testings detect different nerve fiber defects. The weak correlation between these tests indicates the need to use more than one test in screening for diabetic neuropathy.

Inhibitory effect of islet amyloid polypeptide of glucose-induced proinsulin biosynthesis in rat insulinoma cells.

Islet amyloid polypeptide (IAPP) has been recently identified as the principal constituent of amyloid deposits in pancreatic islets of patients with type 2 (non-insulin-dependent) diabetes mellitus and causes insulin resistance in some target cells. In addition, glucose-induced insulin secretion is inhibited by IAPP. We studied the effect of IAPP on proinsulin biosynthesis in rat insulinoma (RINr) cells. Glucose at concentrations of 0, 15, 30, 60, 100, and 300 mg/dl stimulated proinsulin biosynthesis in a dose-responsive and and actino-mycin D-inhibitable manner after 6 h of incubation. At a glucose concentration of 300 mg/dl, IAPP decreased the mean responses of proinsulin biosynthesis to 61.2 and 29% at concentrations of 0.1 and 1 microM, respectively, compared with the IAPP-free control. In conclusion, IAPP inhibits glucose-induced proinsulin biosynthesis in RINr cells. IAPP might play an important role in the pathogenesis of type 2 diabetes mellitus.

A rapid method to study heat shock protein 70-2 gene polymorphism in insulin-dependent diabetes mellitus.

To examine the role of DNA loci within the human leukocyte antigen (HLA) region and insulin-dependent diabetes mellitus (IDDM), we studied fine mapping of HSP70-2 gene. Polymerase chain reaction (PCR)-based genotyping was then developed and applied to type HSP70-2 in 59 patients with IDDM and 83 unrelated controls recruited from the inhabitants of northern Taiwan. Southern blot analysis revealed a diallelic PstI polymorphism of the HSP 70-2 gene, i.e., 9.6- and 8.5-kb alleles. The polymorphic site was mapped in the intragenic PstI sequences (nucleotides 1051-1056) of the HSP70-2 gene. PCR-based restriction fragment length polymorphism studies revealed that the frequency of the 8.5-kb allele was increased in IDDM (56.8%, vs. 40.4% in controls; p < 0.009), with a relative risk of 1.93 (95% confidence interval = 1.20-3.11). The genotypic frequencies of 9.6/9.6, 9.6/8.5, and 8.5/8.5 were 17.0, 52.5, and 30.5% for IDDM were different from those of controls (36.1, 47.0, and 16.9%, respectively; the homozygous 9.6/ 9.6 genotype was significantly decreased in the IDDM group, p < 0.02). In conclusion, we provide a simple, rapid, and nonradioactive method for HSP70-2 genotyping. Our data confirmed that the 8.5-kb allele of HSP70-2 was associated with IDDM susceptibility in the Taiwanese population.

Screening for the Gly40Ser mutation in the glucagon receptor gene among patients with type 2 diabetes or essential hypertension in Taiwan.

As a major counterregulatory hormone of insulin, glucagon plays an important role in regulating glucose homeostasis through its binding to the glucagon receptor. Recently a missense mutation in the glucagon-receptor gene (Gly40Ser) was found to be associated with type 2 diabetes in France and Sardinia, with a frequency as high as 4.6% and 8.3%, respectively. This mutation was also found to be associated with essential hypertension in the white population with a frequency of 5.4%. To investigate the role of this mutation in the pathogenesis of type 2 diabetes and essential hypertension in Taiwanese population, we screened 121 normal controls, 213 unrelated subjects with type 2 diabetes, and 107 unrelated subjects with essential hypertension by use of polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). None of the Taiwanese subjects recruited in the study had this receptor mutation. Our results demonstrate a strong genetic heterogeneity among the ethnic group and suggest that the Gly40Ser mutation of the glucagon receptor gene plays little role, if any, in the pathogenesis of type 2 diabetes and essential hypertension in the Taiwanese population.

Mitochondrial gene mutations in patients with insulin-dependent diabetes mellitus in Taiwan.

We studied the prevalence of mitochondrial gene mutations in subjects with insulin-dependent diabetes mellitus (IDDM) in a Chinese population living in Taiwan. Eighty-four subjects with insulin-dependent diabetes mellitus and 105 unrelated normal controls were recruited in the present study. Both an A-to-G mutation at position 3243 and a mutation at position 8,344 of the mitochondrial DNA were screened by polymerase chain reaction-restriction fragment length polymorphism methods and confirmed by direct DNA sequence analysis. The insulin secretory response was assessed by the C-peptide response to glucagon administration. Among 84 IDDM patients, two (2.4%) subjects were found to carry the 3,243 nucleotide pair (np) mutation. There was no np 8,344 mutation in this series. Of the two subjects carrying a mitochondrial gene mutation, case 1 manifested initially as gestational diabetes mellitus. Manifestation of case 2 was consistent with MELAS, a syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The pancreatic beta cell reserve was reduced, as the glucagon-stimulated C-peptide response was very low in these two cases. HLA genotyping studies revealed that case 2 carried DRB1*0301-DQA1*0501-DQB*0201/ DRB1*0405-DQA1*0301-DQB1*0302, which was the most susceptible genotype to IDDM in our population. Anti-GAD65 antibody was also positive in this patient. In addition to the nuclear genes, a defective mitochondrial gene might contribute to some of the clinical cases with IDDM.