Hideo Manaka

Hypersecretion of Truncated Glucagon‐like Peptide‐1 and Gastric Inhibitory Polypeptide in Obese Patients

Postprandial insulin secretion is modulated by both neural and humoral gastrointestinal insulinotropic factors in addition to the absorbed nutrient. To investigate the involvement of the potent insulinotropic hormones gastric inhibitory polypeptide (GIP) and truncated glucagon‐like peptide‐1 (tGLP‐1) in the postprandial hyperinsulinaemia of obesity, we examined the changes in plasma levels of GIP and tGLP‐1 by an oral glucose tolerance test (OGTT) in nine normal subjects (controls), nine obese subjects without glucose intolerance (Group A), and six obese mild diabetic patients (Group B). Following the OGTT, plasma GIP levels in Group B were increased more markedly than those in the other two groups. Plasma levels of tGLP‐1 were estimated by the difference between the values measured with the N‐terminal directed antiserum (GLP‐1NT) and those with the C‐terminal directed antiserum (GLP‐1 CT). Plasma levels of GLP‐1 NT were increased in Group B, but decreased in the other two groups. Plasma GLP‐1 CT levels were increased in all groups with the highest response in Group B. These results suggest that the combined augmentation of plasma GIP and tGLP‐1 responses were involved in the delayed and considerable increases in plasma insulin after glucose ingestion in obese diabetic patients. Since tGLP‐1 is suppressed in the hyperglycaemic hyperinsulinaemic state in normal subjects, the augmented tGLP‐1 response appears to be characteristic of obese Type 2 diabetes.

Prevalence of Diabetes and Impaired Glucose Tolerance in Funagata Area, Japan

OBJECTIVE To determine the prevalence of diabetes mellitus and IGT in the Funagata area of Japan. RESEARCH DESIGN AND METHODS The total eligible subjects was 1163, all were > or ≥45 yr of age, and 52 were known diabetic patients. Data collected included body height, weight, and answers to medical questionnaires. A 75-g OGTT was done in the morning. WHO criteria were used to classify the current diabetes status of study participants. RESULTS Of the 1111 scheduled for the OGTT, 868 took the test; the participation rate was 77.8%. The prevalence of diabetes was 10.5 and 12.9%, and the prevalence of IGT was 14.7 and 18.0% for men and women, respectively. The prevalence of undiagnosed diabetes (4.9%) was almost equal to that of previously diagnosed diabetes (4.5%). CONCLUSIONS The prevalence of diabetes in the Funagata area was two to four times higher than that of previous reports in Japan, in which many investigators used a urinary glucose test as a preliminary test. This difference is attributed to the method of determining the prevalence of diabetes.

Calpain 10 gene polymorphisms are related, not to type 2 diabetes, but to increased serum cholesterol in Japanese

A G-to-A (UCSNP-43) polymorphism of the calpain-10 gene was significantly associated with type 2 diabetes (DM) in Mexican-American, and was postulated, together with a T-to-C (UCSNP-44) polymorphism, as a risk factor for DM. We examined the association of these genotypes with DM in Japanese. Eighty-one subjects with DM and 81 non-diabetic subjects (NGT) were recruited. The number of subjects with genotypes UCSNP-43 G/G, G/A and A/A were 76, 5 and 0, respectively, for the DM and NGT groups. The number of subjects with genotypes UCSNP-44 T/T, T/C and C/C were 66, 14 and 1 for the DM group and 64, 17 and 0 for the NGT group. There was no difference between the groups in terms of frequency of any genotype combinations. No association between the genotypes and DM was observed. We next examined the differences between the genotypes or genotype combinations in terms of the traits related to DM, obesity, hypertension and dyslipidemia. No differences were observed between the genotypes UCSNP43 G/G and G/A, between UCSNP-44 T/T and the others, or between the genotype combination UCSNP-43 G/G and UCSNP-44 T/T and the others, except that the individuals with the genotype combination had significantly increased serum cholesterol levels (212.6 +/- 34.3 vs. 198.5 +/- 29.9, P=0.020). The genotype combination might be a risk factor, not for DM, obesity and hypertension, but for increased serum cholesterol.

Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in a rural area of Japan The Funagata diabetes study

PURPOSE To determine the prevalence of type 2 diabetes and impaired sucrose tolerance (IGT) among people aged 40 and over in a rural area, Funagata, Japan, by using a 75-g oral glucose tolerance test (OGTT), and to compare the prevalence to that obtained from a more urban area, Hisayama, Japan. METHODS AND RESULTS Total eligible subjects for the Funagata study were 3526. Among them, 140 were confirmed to have diabetes judged by the 1985 WHO criteria. A 75-g OGTT was conducted, excluding the 140 known cases of diabetes. The 1985 WHO criteria were used to classify the current diabetes status of participants. The overall participation rate was 74.4%. The prevalence of diabetes (known and newly diagnosed cases combined) was 9.1% for men and 10.8% for women. The prevalence of IGT was 12. 0% for men and 16.5% for women. Age-adjusted prevalence (using 1990 Japanese census) of diabetes and IGT in men in Hisayama is two times higher than in Funagata (12.8% vs. 6.8% for diabetes, 19.5% vs. 10. 3% for IGT). Age-adjusted prevalence of IGT in women in Hisayama is significantly higher than in Funagata. CONCLUSIONS The prevalence of type 2 diabetes among people aged 40 and over is approximately 10% even in a rural area of Japan. Prevalence of diabetes and IGT is much higher in an urban area than in a rural area in Japan.

Stimulation of Truncated Glucagon-Like Peptide-1 Release from the Isolated Perfused Canine Ileum by Glucose Absorption

To elucidate whether glucose absorption is necessary for oral glucose-induced truncated glucagon-like peptide-1 (tGLP-1) release, we examined tGLP-1 release by several stimulants from isolated perfused canine ileum. Glucose and nonabsorbable sugars, sucrose and 2-deoxyglucose (2DG), were intraluminally administrated. Following gel filtration of the perfusate after glucose ingestion, the main component of GLP-1 in the eluate is tGLP-1. Both glucose and tGLP-1 in the effluents increased after the intraluminal administration of 5% glucose, but not by that of sucrose or 2DG. Glucose absorption is more important than contact of glucose with ileal epithelium to stimulate tGLP-1 release.

Hyperglycemia is a factor for an increase in serum ceruloplasmin in type 2 diabetes.

OBJECTIVE To examine if there is a correlation between high blood glucose and serum ceruloplasmin (Cp) levels. RESEARCH DESIGN AND METHODS Serum Cp levels were measured in 637 patients with type 2 diabetes (all type 2 diabetes group). For the follow-up type 2 diabetes group, 161 patients who had not had any changes in their situation during the last year that are known to influence serum Cp levels were reexamined 1 year later. The control group was composed of 158 healthy individuals. Serum Cp and blood HbA1c levels were measured by radial immunodiffusion and high-performance liquid chromatography assays, respectively. RESULTS Serum Cp levels in the all type 2 diabetes group were significantly higher than those in the control group (P < 0.0001), although the serum Cp levels did not correlate with the blood HbA1c levels in the all type 2 diabetes group (r = 0.055, P = 0.351). Then we evaluated those factors (Δ-log Cp and Δ-HbA1c) in the follow-up type 2 diabetes group to minimize changes from the genetic differences and to exclude any known factors influencing serum Cp levels. This indicated that the Δ-HbA1c had a positive correlation to the Δ-log Cp (r = 0.304, P < 0.0001). CONCLUSIONS A persistent high blood glucose (namely HbA1c) is associated with an increase in serum Cp levels over 1 year.

Differences in glucagon-like peptide- 1 and GIP responses following sucrose ingestion

To investigate the mechanism of oral carbohydrate-stimulated secretion of the two most potent incretin candidates, gastric inhibitory polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1), we studied the changes in the plasma levels of these peptides in five healthy men after sucrose ingestion with or without pretreatment with an alpha-D-glucosidase inhibitor (AO-128). After sucrose ingestion, plasma levels of GIP peaked at 15 min and remained high up to 120 min. Plasma levels of GLP-1 NT measured with antiserum R1043 (N-terminal specific) tended to decrease gradually and those of GLP-1 CT measured with antiserum R2337 (C-terminal specific) increased. Therefore, estimated plasma levels of tGLP-1 increased markedly within 30 min, then declined slightly over the next 60 min. After treatment with AO-128 (0.6 mg/day) for 1 week, increases in plasma glucose and insulin levels were attenuated and the increase in plasma GIP levels was diminished, while the increase in tGLP-1 levels was sustained much longer. It is concluded that GIP secretion is stimulated by glucose absorption and tGLP-1 secretion by the presence of sucrose in the gut.

Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt-Jakob disease

We have established the radioimmunoassay for ubiquitin in the cerebrospinal fluid (CSF) and measured the ubiquitin concentration in CSF from 4 cases of neuropathologically verified Creutzfeldt-Jakob disease (CJD), 10 cases of multi-infarct dementia (MID), 7 cases of senile dementia of Alzheimer type (SDAT), and 18 controls. The normal values were determined to range from 7.3 to 21.0 ng/ml, 14.3 +/- 1.1 ng/ml in the mean +/- S.E.M. The CSF ubiquitin levels in the cases of MID and SDAT were 16.6 +/- 6.4 ng/ml and 21.3 +/- 6.1 ng/ml, respectively. In the cases of CJD, the CSF ubiquitin was markedly increased at the early and middle stages of the disease (230.6 ng/ml in Case 1, 107.6 ng/ml in Case 2, 212.5 ng/ml in Case 3, and 377.0 ng/ml in Case 4) and these gradually decreased as the disease progressed. The measurement of CSF ubiquitin seems useful to make an early diagnosis of CJD.

Acute intermittent porphyria with central pontine myelinolysis and cortical laminar necrosis.

Abstract Acute intermittent porphyria (AIP) is an autosomal-dominant disease caused by a deficiency of porphobilinogen (PBG) deaminase. Patients with AIP present with neurological syndromes such as autonomic neuropathy, peripheral axonal neuropathy or central nervous system dysfunction. We report serial MRI of a patient with AIP who had cortical and subcortical cerebral changes. A 29-year-old woman with a 6-month history of AIP had an attack with severe hyponatraemia and generalised convulsions, treated with haem arginate and supportive therapy. MRI showed central pontine and extrapontine myelinolysis and cortical laminar necrosis. These are not common in AIP, but are likely to have been caused by rapid correction of hyponatraemia and by vasospasm, which could be induced by AIP.

Response of truncated glucagon-like peptide-1 and gastric inhibitory polypeptide to glucose ingestion in non-insulin dependent diabetes mellitus : effect of sulfonylurea therapy

Gastric inhibitory polypeptide (GIP) and truncated glucagon like peptide-1 (tGLP-1) are potent gastrointestinal insulinotropic factors (incretin), mostly released after a meal or ingestion of glucose in man and animals. To investigate whether sulfonylurea (SU) affects the secretion of incretin, the modulation of plasma GIP and tGLP-1 levels following glucose ingestion in non-insulin-dependent diabetic type 2 patients with or without SU therapy was studied. A 75-g oral glucose tolerance test (OGTT) was carried out on 9 healthy subjects (controls) and 18 patients with non-obese type 2, 9 of whom were treated by diet alone (NIDDM-diet) and the other 9 with SU (glibenclamide 2.5 mg or gliclazide 40 mg) once a day (NIDDM-SU). Plasma GIP was measured by radioimmunoassay (RIA) with R65 antibody, and GLP-1 was measured by RIA with N-terminal-directed antiserum R1043 (GLP-1NT) and C-terminal-directed antiserum R2337 (GLP-1CT). Following OGTT, plasma glucose, GIP, GLP-1NT, and GLP-1CT in type 2 patients increased more markedly than in controls, despite the lower response of insulin. However, there were no significant differences in plasma levels of these peptides between the NIDDM-diet and NIDDM-SU groups. Therefore, it is unlikely that SU is involved in the high response of GIP and GLP-1s to OGTT in type 2 patients.