Ryoko Hagura

Insulin Responses in Equivocal and Definite Diabetes, with Special Reference to Subjects Who Had Mild Glucose Intolerance but Later Developed Definite Diabetes

Insulin secretory responses during the 100-gm. glucose tolerance test (GTT) were studied in subjects who had or had had glucose intolerance. Patients who had metabolic diseases other than diabetes were excluded. The ratio (ΔIRI/ΔBS) of increments of blood insulin to blood sugar 30 minutes after glucose load was used as the most sensitive index to detect the abnormality of early Insulin release In diabetes. In patients with definite diabetes (I.e., those whose fasting blood sugar values (FBS) were or had been higher than 140 mg./lOO ml. or who had diabetic retinopathy), ΔIRI/ΔBS ratios were almost invariably subnormal regardless of FBS levels and the types of glucose tolerance at the time of GTT. In the rest of the patients (equivocal diabetics), ΔIRI/ΔBS ratios were either normal or subnormal. The decrease in ΔIRI/ΔBS was a fairly stable characteristic of each individual; in 330 equivocal diabetics, only 28 cases (8.4 per cent) moved between high-and low-insulin-responder groups during the follow-up. In 39 patients who had equivocal diabetes at the initial examination but subsequently developed definite diabetes (20 who began to have FBS above 140 mg./lOO ml. and 19 who developed retinopathy), the insulin response were already subnormal at the initial GTT and remained low throughout the follow-up periods, although their glucose tolerance varied between normal, borderline, and diabetic types. Thus, definite diabetes occurred exclusively in the low-insulin-responder group among equivocal diabetics. The decrease in insulin response to glucose seems to be a more Inherent, specific, and stable feature of true diabetes than glucose intolerance, because it precedes the occurrence and persists after the remission of derangement of carbohydrate metabolism in definite diabetes.

Characteristics of cranial nerve palsies in diabetic patients.

The incidence of palsy in the third, sixth and seventh cranial nerves was studied with regard to central nervous system involvement in diabetic patients. Among 1961 diabetic patients, 19 (0.97%) demonstrated cranial nerve palsies. Nine out of these 19 patients showed facial palsy; 6 palsy of the oculomotor nerve; 2 palsy of the abducent nerve; and 3 both oculomotor and abducent nerve palsies. In contrast, only 5 out of 3841 non-diabetic patients (0.13%) had any cranial nerve palsies; all 5 were cases of facial palsy. The incidence of cranial palsies in diabetic patients was significantly higher than that in non-diabetic patients (P less than 0.01). Concerning age, sex, the state of glycemic control, diabetic complications and method of treatment, there were no differences disclosed in the diabetic patients with cranial nerve palsy. The incidences of diabetic complications were compared between the patients with facial palsy and those with ophthalmoplegia. Only one out of 9 patients with facial palsy (11%) had diabetic complications, whereas 7 out of 10 patients with ophthalmoplegia (70%) demonstrated diabetic complications and the difference was significant. Thus ophthalmoplegia appears to be more closely related to diabetic metabolism while facial palsy is less strongly correlated with diabetes.

Abnormal Secretion of Insulin and Glucagon by the In Vitro Perfused Pancreas of the Genetically Diabetic Chinese Hamster

Hereditary insulin-deficient diabetes mellitus occurs in certain sublines of nonobese Chinese hamsters. Several characteristics of this syndrome are similar to those seen in insulin-deficient human diabetics. Therefore, to characterize pancreatic islet function, dynamic insulin and glucagon release from normal and nonketotic diabetic hamster pancreases in response to glucose (300 mg/100 ml) and theophylline (10 mM), infused singly and together, was studied in vitro.20-min glucose infusions of normal hamster pancreases caused biphasic insulin release, consisting of a rapid first peak and a gradually rising second phase, similar to that reported for man in vivo. Both phases were significantly reduced in the diabetic pancreases. Theophylline alone stimulated similar nonphasic insulin release in both the normal and the diabetic pancreases. Glucose and theophylline together caused greater insulin release than either stimulant alone in both normals and diabetics; however, the diabetic response was still subnormal. Glucose suppressed glucagon release from normal pancreases; suppression was significantly impaired in diabetics. Theophylline stimulated nonphasic glucagon release in both the normals and diabetics. Glucose partially suppressed the theophylline-stimulated release in both groups.Insulin/glucagon molar ratios of the diabetics were consistently subnormal, although individual hormone levels often overlapped into the normal range. IN SUMMARY, THE PANCREASES OF GENETICALLY DIABETIC CHINESE HAMSTERS PERFUSED IN VITRO SHOWED: (a) decreased first and second phase insulin release in response to glucose-containing stimuli-only partially ameliorated by theophylline-, and (b) impaired suppression of glucagon in response to glucose, resulting in (c) a decreased insulin/glucagon molar ratio. These data support the suggestion that both alpha and beta cells of diabetic pancreases may be insensitive to glucose.

Comparison of the Inhibitory Effects of Diphenylhydantoin and Diazoxide Upon Insulin Secretion from the Isolated Perfused Pancreas

Both diazoxide and diphenylhydantoin have been shown to cause hyperglycemie in man and to inhibit insulin secretion in vitro. The effects of these two drugs upon the response to 300 mg./100 ml. glucose were contrasted in the isolated, perfused rat pancreas. Similarities: Both drugs inhibited within seconds. At high concentrations (75 μg./ml.) of either drug, 95 to 100 per cent inhibition occurred. Upon withdrawal, return of secretion was rapid. Differences: During constant (five- and twenty-minute) infusions of diazoxide (10 to 75 μg./ml.), there was an initial fall in secretion and then an “escape” toward pre-inhibition levels; after diazoxide there was a postinhibitory overshoot. In contrast, five-minute infusions of diphenylhydantoin (5 to 75 μg./ml.), and twenty-minute infusions of 25 to 75 μg./ml., though causing comparable levels of initial inhibition, did not cause escape or postinhibitory overshoot. However, an incompletely inhibitory concentration of diphenylhydantoin (10 μg./ml.), given for twenty minutes, was followed by this overshoot. Computer simulation, based on the compartmental-quantal model, suggested that diphenylhydantoin inhibits both secretion from a labile insulin compartment and provision of insulin and/or precursor to this compartment. Lower, partially inhibitory concentrations (i.e. 10 μg./ml.) of diphenylhydantoin might allow for some provision to proceed, and thus a postinhibitory overshoot would occur. The escape and overshoot noted with all inhibitory levels of diazoxide, when compared with the simulations, suggested that this drug may act primarily to inhibit a late step in the provisionary phase.

Risk factors for the development of diabetic retinopathy in Japanese type 2 diabetic patients

This study investigated the risk factors for development of diabetic retinopathy (DR) in 787 type 2 diabetic patients with no retinopathy at the first visit. The subjects were followed up for at least 3 years (mean, 6.7 years). Among the baseline factors, significant correlations were observed between the development of DR and HbA1c (P < 0.0001), the method of therapy (P < 0.005), the duration of diabetes at the first visit (P < 0.005) and the past maximal body mass index (BMI) (P < 0.01). No significant correlation was found with the blood pressure, age, gender, TC or BMI. Among the follow-up variables, the mean HbA1c (P < 0.0001) and duration of diabetes (P < 0.001) correlated significantly with DR development, whereas the blood pressure and age did not. We found that a 1% decrease in HbA1c led to a 35% reduction in the risk of development of DR during the follow-up. The patients whose HbA1c at the first visit was higher than the median value of 8.2% showed a higher probability of development of DR during the next 3 years even when the same blood glucose control was maintained during the follow-up. In conclusion, our study demonstrated that the most important risk factor influencing the development of DR was the blood glucose control. Moreover, we found that the glycemic level at the first visit also influenced the development of DR.

Sequence Variations of the Glucokinase Gene in Japanese Subjects With NIDDM

Mutations in the glucokinase gene have been identified recently in patients with maturity-onset diabetes of the young, a subtype of NIDDM. The proposed role of glucokinase as a glucose sensor, combined with the low insulin response to glucose found in most Japanese with NIDDM, prompted us to speculate that mutations in the glucokinase gene might be one of the major causes of NIDDM in Japanese subjects. To determine the prevalence of mutations and sequence variations in the glucokinase gene, we screened all 12 exons of the glucokinase gene, including exon/intron junctions, by polymerase chain reaction followed by single-strand conformation polymorphism in 209 Japanese NIDDM subjects. In addition to the mutation in exon 7, which substituted Arg (AGG) for Gly (GGG) at codon 261 (10), a silent mutation of Pro (CCC→CCG) in exon 4 at codon 145 and several new sequence variations in intervening sequences and the 5′-untranslated region of exon 1β (β-cell-specific exon 1) were identified. Because we identified only one subject who had a structurally abnormal glucokinase molecule, we conclude that the prevalence of structural mutations in the glucokinase gene responsible for NIDDM appears to be rare among Japanese patients. To our knowledge, this is the first thorough study describing the ethnic prevalence of mutations and sequence variations in the glucokinase gene in NIDDM.

Serum gliclazide concentration in diabetic patients: Relationship between gliclazide dose and serum concentration

Serum levels of gliclazide were determined by radioimmunoassay in seven healthy controls and in 18 diabetic in-patients receiving single oral dosing and consecutive dosing over 5 days. Following a single oral dose of 40 mg in the seven controls and eight diabetic patients, and 120 mg in ten diabetic patients, the serum levels of gliclazide peaked on average at 2 h, followed by a slow decline, the t1/2 being 16.5 h in the volunteers, 12.3 h in the diabetic patients receiving 40 mg, and 10.5 h in those receiving 120 mg. During consecutive administration, the serum levels both at fasting and at the peak reached a plateau in 2 days and no further accumulations were observed. The steady-state peak levels of gliclazide in the diabetic patients revealed a strongly positive correlation with the dose per m2 body surface area (r = 0.78, P less than 0.001), and their steady-state fasting levels correlated positively but weakly with the dose per m2 body surface area (r = 0.48, P less than 0.05). Thus, measuring either the fasting or the peak concentration of gliclazide will be useful for monitoring drug concentration in the serum. Pharmacokinetics of gliclazide will contribute to the elucidation of the relationship of serum level and clinical effectiveness in diabetic subjects.

Insulin secretory response in Japanese type 2 (non-insulin-dependent) diabetic patients

Insulin (immunoreactive insulin, IRI) response during a 100 g oral glucose tolerance test was studied in a large number of patients with definite diabetes, equivocal diabetes, and other pathological states causing glucose intolerance. Definite diabetes was diagnosed in patients with overt fasting hyperglycemia. Once the diagnosis of definite diabetes was made, IRI response remained low after improvement of glucose tolerance. Glucose intolerance caused by other pathological extra-pancreatic conditions was usually accompanied by increased IRI response. IRI response in equivocal diabetes was variable, but almost always decreased in those who developed definite diabetes later. In subjects with a strong family history of type 2 diabetes, the prevalence of a low IRI response was high. In non-diabetic subjects, weight gain caused a marked increase in IRI response and a small increase in blood glucose, while in those who developed diabetes, IRI increased little despite the marked increase in blood glucose. These data suggest that low IRI response is an important feature of type 2 diabetes, perhaps with a hereditary basis in part. It precedes the occurrence of overt hyperglycemia and persists after improvement of glucose tolerance.

Screening and follow-up of diabetic retinopathy using a new mosaic 9-field fundus photography system

AIM To evaluate the clinical usefulness of a newly developed fundus photographing system and assess its applicability to telemedicine. METHODS Nine overlapping 45 degrees fundus photographs were taken by a new camera equipped with nine internal fixation targets to provide standardized 9-field photographs. The digitally stored images were either edited in 3x3 form or reconstructed as collage (9F) and compared to the ophthalmological examination (OP) and single-field non-mydriatic photography (SC). In telemedicine, 9-field images derived from 61 adolescent diabetics were sent to ophthalmologists over an analog phone line. RESULTS The sensitivities of the examinations by 9F without and with mydriasis (78 and 82%) were equivalent to OP (84%) and superior to SC (64%). The diagnosis of severity by 9F was also comparable to those by OP, whereas SC tended to underestimate the severity. An average of 1 min 19 s was required to send one edited 9-field photography (average size 259+/-30 KB) over the Internet. Twelve of these eyes were diagnosed as diabetic retinopathy on a desktop monitor whereas SC gave only seven. CONCLUSION This new 9-field fundus photography system can be appropriate for the screening and follow-up of diabetic retinopathy in adult and adolescent diabetic subjects, especially when applied to telemedicine over the Internet.

Family histroy of diabetic patients in Japan

The frequency of a positive family history of diabetes in diabetic patients has increased in recent studies. In this study, it was 16-33% for type 1 diabetes and 43-49% for type 2 diabetes. It was significantly higher than in non-diabetic subjects, and in type 2 than in type 1 diabetic patients. The prevalence of diabetes in parents and siblings of type 2 diabetic patients was higher than in those of type 1 patients, and it was particularly high in parents of young onset type 2 patients. Among type 2 diabetic patients, positive family history was somewhat lower in those with marked obesity in the past. Comparison of groups with varying degrees of glucose intolerance revealed that a family history of diabetes increased in parallel with the impairment of glucose tolerance. The results suggest that genetic factors in the pathogenesis of diabetes are more important in type 2 than in type 1 diabetes, and in the younger onset and less obese subjects than in older onset and more obese patients for type 2 diabetes.