The term “entero-insular axis” originally denotes the potentiation of insulin secretion by gut factor (s) during the oral glucose tolerance test (OGTT) when compared with the intravenous glucose tolerance test (IVGTT).
On the basis of the determination of the plasma insulin/c-peptide molar ratio, however, it has recently been proposed that the hepatic insulin extraction decreases when glucose is given orally, and peripheral hyperinsulinemia ensues.
To confirm and extend this further, the OGTT (75 g glucose) was performed first, followed by the IVGTT (30 g glucose) one week later, in the same individuals, i.e., five normal controls (N), 11 obese subjects (O), nine type 2 diabetics (D) and six patients with liver cirrhosis (L).
The summed insulin increment (εΔ IRI) as well as plasma glucose (εΔ BS) was much greater in the OGTT than in the IVGTT in both the D and L groups, while in the N and 0 groups, a larger εΔ IRI was found during the OGTT even in the absence of any difference in εΔ BS. At least one of the following indices including CPR as a variable, IRI/CPR, εΔIRI/εΔ CPR, and ΣΔIRI/urinary CPR, was significantly higher during the OGTT in all groups except the group of liver cirrhosis. Interestingly in this group, all three indices relating to the IRI/CPR ratio were almost comparable between the OGTT and the IVGTT.
Providing that C-peptide is secreted from the pancreas equimolarly to insulin and its hepatic removal is negligible, these findings suggest that the reduction of hepatic insulin extraction, together with true enhancement of insulin secretion into the portal vein, is one of the factors contributing to hyperinsulinemia observed during the OGTT.

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The levels of fasting serum total ketone bodies (TKB), acetoacetate (AcAc), and 3-hydroxybutyrate (3-OHB) in diabetics were determined by the diazonium method to evaluate the significance of these measurements in diabetes mellitus (DM). The following results were obtained:
1) The diabetics studied were shown to have significantly higher levels of TKB, AcAc, 3-OHB and 3-OHB/AcAc ratio than those in normal subjects. The same results were also obtained in type 11 DM patients treated by dieting alone whose fasting blood glucose levels were well controlled.
2) The levels of TKB, AcAc, and 3-OHB were higher in type II DM patients who were under poor blood glucose control had a high level of free fatty acid and a lowered insulin secretion capacity (ΣΔCPR120').
3) The levels of TKB, AcAc, and 3-OHB in diabetics showed a significant positive correlation with glucagon: insulin (IRG/CPR) molar ratio.
These findings indicate that the levels of fasting serum ketone bodies in diabetics are useful as one of the most important indices for the management of DM.

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Fructose-lysine linkage is formed by the non-enzymatic binding of glucose to the s-amino group of lysine in plasma protein. Furosine derived from fructose-lysine of plasma protein by acid hydrolysis was identified by HPLC for the estimation of glycosylated plasma protein (GPP). An equimolar amount of glucose was added to a lysine solution. Then the mixture was heated at 100°C for 1 hour and was hydrolyzed in 6 mol/l HCL at 95°C for 30 hours. Hydrolysates of plasma proteins from nondiabetics and diabetics were determined by HPLC using a μ Bondapak C₁₈ column. The area under the furosine peak which appeared at a retention time of 4.1 minutes under the following chromatograhic conditions was measured: flow rate, 1 ml/min; UV detector wavelength, 280 nm and 254 nm. The furosine appeared at a peak height A 280 nm/A 254 nm ratio of 3.9. This peak could not be found by reduction with NaBH₄ prior to hydrolysis. Therefore, this peak was considered a peak of furosine. The tyrosine peak was used as an internal standard. The levels of GPP were expressed as the ratio of furosine peak area to tyrosine peak area, i.e., furosine/tyrosine × 100 (%). The intra-assay and inter-assay coefficients of variation of furosine values were I. 4% and 3.6%, respectively. GPP values paralleled plasma protein concentrations. GPP values reached a plateau at a content of 30 mg plasma protein and after 24 hours' hydrolysis. The furosine value of GPP was 4.6 ±1.5%(mean ± S.D.) in diabetics, significantly higher than that in normal subjects, i.e., 2.6 ± 0.5%. A significant positive correlation was found between GPP and fasting blood glucose (r= 0.66, p<0.001) or HbA₁ (r=0.62, p<0.001) The results indicate that furosine derived from fructose-lysine in glycosylated plasma protein may become an indicator of long-term blood glucose control in diabetic patients.

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The skin blood flow (Periflux blood flow: PBF) in the finger tip was measured with a Periflux laser doppler flowmeter (PLDF). PLDF is a new instrument for the direct, continuous and noninvasive measurement of blood flow in skin capillaries. A 2 m W He-Ne laser was used as a light source. In the present study, the pattern of PBF was evaluated as a measure of autonomic neuropathy in diabetic patiens. Response to the Valsalva maneuvre was studied in 80 normal subjects and 93 diabetic patiens. PBF decreasing velocity (PDV) was chosen as an index of the PBF response. The results obtained were as follows.
1) In normal subjects, PDV value was decreased significantly by atropine sulfate, but it was not affected by age, sex or the duration of breath holding.
2) PDV value (mV/sec) was 134 ±41 (mean ± SD) in normal subjects, and 75±50 (mean ± SD) in diabetic patients. The frequency with which abnormal PDV occurred in diabetic patients was 45%(42/93 cases).
3) Twenty-one diabetic patients were examined with regard to Beat-to-beat variation (BBV). There was significant correlation between PDV and BBV (r=0.802. p<0.001).
These results suggest that measurement of PBF observed by the Valsalva maneuvre is clinically useful for evaluating parasympathetic nerve dysfunction in diabetic patients.

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Islet cell surface antibodies have been detected in the sera of many patients with insulindependentdiabetes. Autoantibodies against the islet cell plasma membrane are detected mainly by indirect immunofluorescence and ¹²⁵I-protein A binding assays. We therefore compared these assay methods, using rat islet cells and a human islet cell line (JHPI-1) as antigenic cells.
In indirect immunofluorescence of both the rat cells and the JHPI-1 cells, there was a good correlation between fixed and living cells (p<0.05). After fixation with paraformaldehyde, some antigens on rat islet cells may have been damaged and no correlation was observed between the rat and JHPI-1 cells. In the ¹²⁵I-protein A binding assay, there was a good correlation between fixed and living cells of JHPI-1 (p<0.01).
In comparing the results of immunofluorescence and ¹²⁵I-protein A binding assays, a difference was observed in the islet cell surface antibody titers in the rat and JHPI-1 cells.
It is concluded that these assays of islet cell surface antibodies are limited to measuring the amount of autoantibodies.

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The operative results and left ventricular function were compared in diabetic (29 cases) and non-diabetic subjects (63 cases) who had undergone aortocoronary (A-C) bypas surgery. The rate of patency of the A-C bypass graft was lower in the diabetic (80.2%) than in the non-diabetic group (92.0%). Mean graft flow measured during the surgery was 44 m//min in the diabetic group. This was significantly lower than that of the non-diabetic group (57 m//min). The number of coronary arteries with resistance of more than 100 mmHg/m//sec was significantly larger in the diabetic group than in the non-diabetic group. There was no significant difference in the ejection fraction and the end-diastolic pressure of the left ventricle before and after the surgery in either of the two, groups.
The heart rate and double product increased, significantly after the surgery in both groups, but the rate of increase was more pronounced among the diabetics. The ejection fraction of the left ventricle did not improve postoperatively in the diabetic group, whose ejection fraction was 60% or less. But it increased significantly after the surgery in the non-diabetic group. Fractional shortening was significantly increased after the surgery in the non-diabetic group, in whom aortocoronary bypass operation had been performed on the anterior descending branch of the left coronary artery and the patency of the graft had been ascertained by postoperative coronary angiography. But it did not improve significantly in the diabetic group.
Thus, it was concluded that the rate of patency of the graft and the grade of improvement of the left ventricular function were significantly worse in the diabetic than in the non-diabetic group.
As a result, it was considered that the A-C bypass operation in diabetic patients should be restricted to those with absolute indications.

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Ten guinea pigs were inoculated with porcine monocomponent insulin on days 0, 13, 22 and 58. Serial antisera obtained 22 days after the first inoculation were pooled and anti-insulin antibodies were purified by passing them through an insulin-epoxy-sepharose 6 B column. After extensive dialysis against 0.1 M NaH₂PO₄, pH 3.0, followed by extensive dialysis against PBS, anti-insulin antibodies were inoculated subcutaneously on days 0, 8, 15 in two Japanese white rabbits (API-1, API-2) with FCA. Antisera obtained 18 days after the first inoculation were tested for the presence of anti-insulin antibodies first. Because weak anti-insulin antibody activities were noted, both antisera were passed through insulin-epoxy-sepharose 6 B to remove anti-insulin antibody activities in them. Antisera thus obtained were examined for the presence of anti-insulin anti-idiotypic antibodies.
Antisera from API-1 and API-2 in the γ-globulin concentrations of 3 γ 10^-1 mg and 6.7 γ 10^-1 mg inhibited the binding of ¹²⁵I-insulin with anti-insulin antibodies which had been covalently attached on sepharose 6 B up to 82.7% and 81.7%, respectively. On the other hand, rabbit antiguinea pig IgG and IgM did not interfere with the interaction between 125 I-insulin and antiinsulin antibodies. These results clearly indicate the presence of anti-insulin anti-idiotypic antibodies in the sera from both rabbits. The clinical as well as the basic usefulness of anti-insulin antiidiotypic antibodies is discussed.

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A 52-year-old man with acromegaly developed overt diabetes mellitus at age of 40. He felt an increase in the size of his hands when he was 20. One year prior to admission, he was told that he had proliferative retinopathy. He had photocoagulation and anterior retinal cryocautery treatment of the left eye, but this did not have the desired effect. He was admitted because of congestive heart failure. He had albuminuria. His blood pressure was 170/112 mmHg. Visual acuity was-0.02 on the left. The patient required 15 units of NPH insulin daily and had a fasting serum glucose level of 120μg/dl. There was no CPR response to glucose or L-arginine. He had elevated baseline serum GH levels (230-300 ng/ml), which failed to be suppressed during the oral glucose tolerance test. L-arginine had no effect on GH levels. An IV injection of 500μg of TRH or 100 ig of LH-RH elicited GH relese. After trans-sphenoidal pituitary adenomectomy, his basal GH levels fell to 2.3-7.0 ng/ml and neithera TRH nor I, H-RH had any effect on GH levels. The patient's insulin requirement decreased to 6 units daily. This operative treatment diminished macular edema and led to the absorption of vitreous bleeding. Visual acuity improved to 0. 2-0.3 on the left, although his serum creatinine level rose.

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The patient was a 27-year-old man who was admitted in an unconscious state on August 16, 1982. Blood glucose level was below 20 mg/dl, and he made a rapid recovery after intravenous administration of glucose.
The presence of insulinoma was suspected because of a high plasma insulin level compared to the blood glucose level.
The 50 g oral glucose tolerance test, L-leucine test, arginine test, glucagon test, and tolubutamide test showed increased insulin secretion compatible with insulinoma. The insulin suppression test (actrapid insulin O.1 U/kg i.v.) revealed that basal blood glucose concentration decreased (the response to exogenous insulin was normal), but that plasma C-peptide concentration was not suppressed and remained high.
Propranolol (30 mg/day P.O.) or diazoxide (200 mg/day P.O.) was given for frequent hypoglycemic attack. Although the blood glucose concentration was not markedly altered by either agent the plasma insulin concentration decreased to some extent on treatment with diazoxide. Propranolol was less effective.
A tumor (22×13 mm) was found in the head of the pancreas and excised at operation.
The ultrastructural appearance of pancreatic tumor cells in some specimens disclosed sparsely distributed secretory granules in the cytoplasma. Futhermore, the tumor was determined to be insulinoma by immunohistochemical staining using anti-human insulin antibody.
We reported a response to diazoxide and propranolol in a patient with insulinoma.

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Nonobese diabetic (NOD) mice aged 30 days were orally treated with Cyclosporin (Cs) at a dose of 25 mg/kg every other day until they were 160 days old. Then 60 day-old mice were treated with Cs at doses of 15 and 2.5 mg/kg every other day until they were 160 days old.
Diabetes developed in 7 of 10 untreated contol mice in the first experiment and 5 of 8 control mice in the second experiment with partial to complete destruction of the islets of Langerhans associated with marked lymphocytic infiltration. The plasma glucose level in control NOD mice gradually increased by the time they were 130 days old and reached 254. 4 ± 93.8 mg/dl (mean±SD) in the first experiment and 335.3± 179. 4 mg/dl (mean ± SD) in the second experiment at 160 days of age, whille Cs-treated NOD mice at any dose showed neither a clear increase in the plasma glucose level nor development of insulitis.
These results suggest that Cs has a preventive effect against diabetes in NOD mice.

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We determined the amount of furosine derived from glucosylated hemoglobin (Hb) by high-performance liquid chromatography (HPLC) by using a reversed phase column chromatograph (TSKGEL) according to the method of Schleicher et al. Forty-four diabetic patients and 7 healthy subjects were selected for the study. Glucose bound to a lysine residue is transformed to fructoselysine which undergoes acid hydrolysis to form furosine. The furosine value of glucosylated Hb (GHb-f) was expressed as the ratio of the furosine peak area to the tyrosine peak area. HbA, was determined by HPLC using an ion exchange column chromatograph (Auto A₁c).
The GHb-f value was 4.6 ± 1.5%(mean ± SD) in diabetic patients, significantly higher than that found in healthy subjects which was 2. 3 ± 0.3%(mean ± SD). A significant positive correlation was found between GHb-f and HbAi values. Furthermore, the GHb-f was best correlated with the stable HbAic value (r= 0.960, p<0.001).
This method is useful for the detection of various glucosylated proteins. In the present study, we evaluated the possible use of furosine as a new indicator of blood glucose control of diabetic patients.

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