I.V. Glucose tolerance test: Correlation between FFA,glucose and IRI in normal,obese and diabetic subjects

Summary Insulin response and FFA behavior have been evaluated during an IVGTT in 63 subjects of whom 18 were normal, 31 were obese (with varying degrees of carbohydrate tolerance) and 14 were mild non insulin-dependent diabetics. The extreme reduction of insulin secretion in the early phase (Δ 0–15 min) and the less severe impairment of the late phase (Δ 15–60 min) have been confirmed; obese subjects showed on the average an active insulin response to venous loading; this was more marked and more consistent in the late phase. Compared to controls, FFA concentration both in basal conditions and during IVGTT was progressively higher in obese and diabetic patients. When analyzing the interplay between IRI, K_G and FFA in the course of IVGTT, it was observed that: (1) a close correlation exists between K_G and early insulin response (r=0.72); (2) a correlation between Δ IRI 0–15 min and percentage decrease of FFA at 45 min is found only in normal subjects; (3) a negative highly significant correlation is found between K_g and mean FFA plasma level 0–60 min. This last correlation is evidence of the important role played by FFA in carbohydrate tolerance. The conflicting results reported by others have been discussed.     

肥胖和非肥胖糖耐量受损患者胰岛素敏感性和1相胰岛素分泌研究

目的研究肥胖和非肥胖糖耐量受损(IGT)患者的胰岛素敏感性和β细胞1相胰岛素分泌功能,以探讨在IGT患者中肥胖对胰岛素抵抗和1相胰岛素分泌的影响。方法共有99位受试者(包括正常对照者32名,肥胖IGT44例,非肥胖IGT23例)接受了口服75 g葡萄糖耐量试验(OGTT)和胰岛素改良的减少样本数(采血样12次)的Bergman微小模型技术结合静脉葡萄糖耐量试验(FSIGTT)。胰岛素抵抗由FSIGTT中胰岛素敏感性指数(SI)加以评估,而OGTT中糖负荷后30 min胰岛素增值与血糖增值之比值[ΔI30/ΔG30=(I30 min-I0 min) /(G30 min-G0 min)]和FSIGTT中急性胰岛素分泌反应(AIRg)则用以评价胰岛β细胞分泌功能。处理指数(DI =AIRg×SI)用于评价AIRg是否代偿机体的胰岛素抵抗。结果与正常对照组[(7.52±10.89)×10-4]相比,二组IGT患者之SI明显降低,而肥胖IGT组的SI[(1.72±1.11)×10-4]较非肥胖组[(3.15±1.49)×10-4]更低(均P<0.01); AIRg和ΔI30/ΔG30在正常组(412±191,14.45±8.47)和肥胖IGT组(378±235,17.02±11.30)之间差异无统计学意义,但均大于非肥胖组(196±160,8.93±6.69,均P<0.01);与正常组(2 851±1 180)相比,DI指数在二组IGT显著降低(595±485,584±517),但后二组间此值差异无统计学意义。SI与2 h胰岛素、体重指数、尿酸和胆固醇呈显著的负相关性(校正r2=0.603,P<0.01);而AIRg与ΔI30/ΔG30显著正相关,与空腹血糖负相关(校正r2=0.479,P<0.01)。结论IGT患者存在胰岛素抵抗和β细胞功能异常。与非肥胖IGT患者相比,肥胖IGT患者胰岛素抵抗程度更为严重,但胰岛β细胞胰岛素1相分泌相对充分。     

The response of serum glucose,free fatty acid and immunoreactive insulin to oral glucose and intravenous tolbutamide in normal,potentially diabetic and diabetic subjects

Summary Glucose, free fatty acids and immunoreactive insulin levels were measured in 323 normal, potentially diabetic and diabetic subjects after an oral glucose load and an intravenous injection of tolbutamide. The results indicate that, in potentially diabetic and diabetic subjects, the insulinogenic response to glucose lasted longer than in normal subjects. It is suggested that this phenomenon be due to the loss of cell sensitivity to the recently demonstrated inhibitory feedback induced by insulin itself. The insulinogenic response to tolbutamide and the FFA response to tolbutamide and insulin did not help in differentiating prediabetic from normal subjects. No consistent relationship was found between body weight and serum insulin response to glucose.This work was aided by Grant No. AM 06034 from the National Institutes of Health and by a Grant from the Upjohn Company.     

Serum and pancreatic immunoreactive insulin (IRI) and proinsulin-like component (PLC), serum IRI and PLC response to different stimuli in normal subjects and organic hyperinsulinism

Summary The serum levels of total immunoreactive insulin (IRI) and proinsulin-like component (PLC) in the fasting state and following the administration of insulin secretagogues in 5 patients with organic hyperinsulinism and age and sex matched normal subjects are reported. Diagnosis of organic hyperinsulinism could be established in all instances on the basis of the inappropriately high total serum IRI levels for the corresponding blood glucose values; such an abnormal relationship was not seen in normal subjects, and was further enhanced by insulin secretagogues. Unrestrained insulin secretion in organic hyperinsulinism was enhanced following the administration of glucose, tolbutamide, glucagon or amino acids; the last 2 stimuli are known to be ineffective in causing insulin secretion in the presence of hypoglycemia in normal subjects. Four patients had insulinomas and one probably had islet cell hyperplasia or abnormal function of islet cells. Chromatography of serum IRI to quantitate PLC is a useful adjunct to the diagnosis of organic hyperinsulinism as in the fasting state the proportion of PLC is always elevated, above the normal range of 5–22%. Following the administration of insulin secretagogues there was pronounced increase in total serum IRI in organic hyperinsulinism but the proportion of PLC generally decreased, suggesting thereby that major increase in IRI was due to release of stored granular IRI which is known to have a low proportion of PLC.     

Postprandial plasma glucose,insulin, glucagon and triglyceride responses to a standard diet in normal subjects

Summary Postprandial plasma glucose, insulin and triglyceride responses were determined in 12 normal subjects (7 male and 5 female) fed a standard diet composed of typical American foods; the three meals were identical for each subject. A significant post-prandial rise in glucose and insulin was observed. They were closely related temporally in the early post-absorptive period. However, in the late post-absorptive phase insulin decline was generally slower than the glucose decline. A considerable difference in the glucose and insulin response was observed between males and females. Fasting plasma glucose and insulin concentrations were lower in the women. Following each meal the peak plasma glucose was lower in the women, but the difference was significant only following breakfast (p < 0.02). The area under the glucose curve following breakfast was also lower (p < 0.01) in the women. In the men the maximal postprandial glucose concentration and the postprandial glucose area remained stable throughout the day, but there was an increase in peak insulin concentration and insulin area after dinner. In contrast, in the women the maximal postprandial glucose concentration and the postprandial glucose area increased throughout the day, but the peak insulin concentration and insulin area did not change. Plasma triglycerides increased with breakfast and remained elevated throughout the day. Both fasting and postprandial mean triglycerides were higher in the men, but this did not reach statistical significance. The circulating pancreatic glucagon concentration, determined in 4 subjects, was unaffected by meals and remained stable throughout the day.     

Feedback inhibition of insulin and glucagon secretion by insulin is altered in abdominal obesity with normal or impaired glucose tolerance

We investigated the feedback inhibition of insulin and glucagon secretion during euglycemic-hyperinsulinemic clamp at about 350 pmol/l in 16 patients with abdominal obesity [8 with normal glucose tolerance (oNGT), 8 with impaired glucose tolerance (oIGT)] and 8 normal-weight subjects matched for age, sex and blood pressure. In oNGT and oIGT, fasting plasma C-peptide levels were twice those in the controls (962±51 and 915±85 vs 439±28 pmol/l,P<0.001) and their suppression was lower than in the controls, both in absolute terms (155±19 and 185±17 vs 274±18 pmol/l,P<0.001) and as a percentage decline from basal levels (16±2% and 21±2% vs 63±2%,P<0.001). Fasting plasma glucagon levels were similar in the patients and in the controls, but were less suppressed during clamp in oNGT and oIGT, both in absolute terms (7.0±0.9 and 5.6±0.6 vs 13.2±1.2 pmol/l,P<0.001) and as a percentage change from basal levels (23±3% and 19±2% vs 44±4%,P<0.001). These results suggest that the insulin feedback on B and A cells is impaired in abdominal obesity, and that this defect is of similar degree in oNGT and oIGT. These alterations could be implicated in the pathogenesis of hyperinsulinemia in obesity.     

Interrelationships of glucose and insulin uptake by muscle of normal and diabetic man

Summary A forearm perfusion technique was used to study glucose and insulin uptake by muscle. In normal subjects at glycaemic levels above 130 mg/100 ml, glucose uptake was independent of glucose concentration; it was directly related to insulin concentration but not to insulin uptake. In non-obese maturity-onset diabetic subjects, glucose uptake was dependent on glucose concentration and insulin uptake, but not on insulin concentration. In both groups there was a strong correlation between insulin concentration and insulin uptake; diabetics had a normal insulin uptake in relation to concentration. For a given change in insulin concentration the increase in glucose uptake was as great in diabetics as in controls, but the effect of insulin was mediated through a mechanism involving its uptake. Thus in the non-obese maturity-onset diabetic, forearm muscle is not insulin resistant. The apparent uptake of insulin measured by a radioimmunoassay in relation to its arterial concentration was lower and more variable for heterologous than for endogenous insulin. With a receptor assay the venous insulin concentrations were lower than with the immunoassay and differences in uptake between endogenous and exogenous insulin disappeared. It is concluded that in muscle exogenous insulin was less severely degraded than endogenous insulin.     

上海地区肥胖糖调节受损者的胰岛素敏感性和1相胰岛素分泌功能研究

目的研究上海地区肥胖的糖调节受损(IGR)者胰岛素敏感性和胰岛β细胞1相胰岛素分泌功能。方法共有129例受试者[非肥胖正常对照38名,IGR包括单独糖耐量受损(IGT)64例,单独空腹血糖受损(IFG)8例,IFG+IGT 19例]接受了口服75g葡萄糖耐量试验和胰岛素改良的减少样本数(n =12)的Bergman微小模型技术结合频繁采血的静脉葡萄糖耐量试验(FSIGTT)。胰岛素抵抗由FSIGTT中胰岛素敏感性指数(S1)加以评估,而FSIGTT中对葡萄糖急性胰岛素分泌反应(AIRg)则用以评价胰岛β细胞分泌功能。处理指数(DI=AIRg×S1)用于评价AIRg是否代偿机体的胰岛素抵抗。结果(1)与正常对照组相比,3组IGR患者之S1明显降低(均P<0．01),3组差异无统计学意义;(2)AIRg在正常组和IGT组之间差异无统计学意义,但均大于IFG和IFG+IGT组,差异有统计学意义(P<0．05或JP<0．01)。IFG +IGT组的AIRg值显著低于IGT组(P<0．01);(3)与正常组相比,DI指数在3组IGR显著降低(P< 0．01),但在IGR组间差异无统计学意义;(4)S1与空腹胰岛素、体重指数、血清尿酸呈显著负相关(校正r2 =0．568,P<0．01);而AIRg与2h胰岛素显著正相关,与空腹血糖、2h血糖和年龄负相关(校正r2=0．402, P<0．01)。结论上海地区肥胖的初诊IGR患者(包括单独IGT、单独IFG和IFG+IGT患者)存在着程度近似的胰岛素抵抗;急性相胰岛素分泌功能在校正胰岛素抵抗影响因素后IGT患者尚属正常,在IFG和IFG+IGT患者已明显降低,且3组的β细胞代偿功能均为一致性失代偿。     

Relationships between insulin secretion after intravenous and oral glucose administration in subjects with glucose tolerance ranging from normal to overt diabetes

Aims Acute insulin release (AIR) in response to intravenous glucose injection (IVGTT) can be abolished in diabetic subjects when their response to oral glucose is maintained. To elucidate this phenomenon, we examined the relationships between fasting plasma glucose (FPG) and the secretory responses to an IVGTT and an oral glucose test (OGTT). Methods We measured AIR and secretion after a 75‐g OGTT in 221 subjects [age 37 ± 11 years, body mass index (BMI) 28 ± 5 kg/m²; mean ± sd ] with normal glucose tolerance (NGT, n = 147), impaired FPG/impaired glucose tolerance (IFG/IGT, n = 28) and Type 2 diabetes (n = 46). Insulin secretion was calculated by C‐peptide deconvolution; pancreatic B‐cell glucose sensitivity was obtained by OGTT modelling. Results Both AIR [186 (185), 142 (164) and 10 (16) pmol/l, median (interquartile range)] and B‐cell glucose sensitivity [98 (64), 66 (53) and 16 (20) pmol min^?1 m^?2 l mmol^?1] decreased across glucose tolerance category (P < 0.0001). However, AIR became ~0 at ~7 mmol/l FPG, whereas B‐cell glucose sensitivity declined gradually throughout the FPG range. In addition, for FPG > 7 mmol/l, AIR was no longer related to FPG, whereas a strong relationship between FPG and B‐cell glucose sensitivity was preserved (ρ = ?0.71, P < 0.0001). In a multivariate regression model, adjusting for sex, age and BMI, glucose sensitivity [standardized regression coefficient (std.r.) = ?0.67, P < 0.0001], but not AIR (std.r. = 0.03, P = 0.55), was an independent predictor of FPG. Conclusions AIR vanishes at fasting or 2‐h glucose levels, at which levels some B‐cell glucose sensitivity is retained; therefore, AIR has a limited ability to quantify B‐cell function in hyperglycaemic states.     

艾塞那肽对糖调节受损肥胖者血胰岛素及胰岛素抵抗的影响

目的探讨艾塞那肽对糖调节受损（IGR）肥胖者血胰岛素及血糖的影响。方法选取2011年5月至2012年11月在福建医科大学附属泉州第一医院就诊的75例糖调节受损（IGR）肥胖者为研究对象,其中62例受试者符合入选条件,按基线胰岛素水平分为高胰岛素血症（HIns,32例）与非高胰岛素血症（NHIns,30例）2组,HIns以空腹胰岛素≥15mU／L和（或）口服葡萄糖耐量试验（OGTr）2h胰岛素≥80mU儿作为切点。测定基线及应用艾塞那肽5d及14d时的空腹与OGTF2h血浆血糖、胰岛素、C肽、体重等指标。以稳态模型评估的胰岛素抵抗指数（HOMA-IR）及Gutt胰岛素敏感指数评估胰岛素抵抗及敏感性。同一组治疗前后比较采用配对t检验,组间均数比较采用单因素方差分析,率的比较采用x。检验。结果两组的空腹及OGTr2h血糖在用药5d时较基线下降（t=4．42、9．78、4．00、8．66,均P〈0．05）,HIns组空腹胰岛素在用药5d时较基线下降（t=2．07,P〈0．05）,OGTr2h胰岛素在用药5d较基线时下降,用药14d较5d时进一步下降（F=24．17,P〈0．05）。HIns组HOMA—IR在用药5d时较基线下降（t=3．27,只〈0．05）。NHIns组HOMA—IR在用药5d及14d时较基线均无下降（均P〉0．05）,HIns组Gutt胰岛素敏感指数在用药5d时较基线升高（t=-9．84,P〈0．05）,14d时较5d时进一步升高（F=55．96,P、遗0．05）。NHIns组Gutt胰岛素敏感指数在用药5d时较基线升高（t=-4．27,P〈0．05）。HIns组与NHIns组体重在5d时较基线无下降,14d时均较5d时明显下降（t=14．13、12．00,均P〈0．05）。结论IGR肥胖人群短期应用艾塞那肽即可获益调节血糖、改善胰岛素抵抗、控制体重。     

Insulinopenia in impaired glucose tolerance preservation of insulin response to i.v. arginine and tolbutamide

Summary Immunoreactive insulin (IRI) response to successive i.v. injections of glucose (0.3 g/kg), arginine (5 g) and tolbutamide (20 mg/kg) was measured in 11 non-obese patients with mild glucose intolerance and 11 control subjects. In 3 of the patients the IRI response to i.v. arginine and subsequent i.v. glucose was also measured. The mean peak IRI level following glucose was grossly diminished in the patients compared to controls but peak IRI levels following arginine and tolbutamide were similar in the two groups. Administering arginine prior to glucose in the 3 patients tested resulted in a lowering of the IRI response to arginine but no increase in the IRI response to glucose. The decreased IRI response to i.v. glucose associated with an adequate response to i.v. arginine and tolbutamide in these patients suggests a failure of the B-cell sensor mechanism for glucose and may provide a physiological explanation for the recognized value of restricting carbohydrate relative to protein in the treatment of this condition. Any defect in the sensor mechanism for arginine appears quantitatively much less severe than that to glucose. Presented in part at British Diabetic Association Meeting, Cardiff, 1977.     

Studies in prediabetes. Insulin response to oral glucose,intravenous tolbutamide and rapid intravenous glucose infusion in genetic prediabetics

Summary Twenty-two non-obese genetic prediabetics (offspring with both parents diabetic) were compared with 34 normal volunteers, closely matched by age and weight, in their response to three standardized stimuli: oral glucose tolerance test (with 100 g of glucose), intravenous tolbutamide tolerance test (1 g) and rapid intravenous glucose infusion (0.33 g/kg body weight). Blood sugar, immunoreactive insulin and non-esterified fatty acids (N.E.F.A.) were estimated in both groups in the fasting state and at different time intervals during each of the three tests. — Results showed no significant differences (either in carbohydrate tolerance or in the behaviour of the N.E.F.A. levels) between normals and prediabetics at any time in the course of the selected tests. Plasma immunoreactive insulin fasting levels were also closely comparable in both groups, no significantly different insulin release in normals and prediabetics being elicited either by the oral glucose load or by the intravenous tolbutamide injection. However, the rapid intravenous glucose infusion brings about a markedly diminished insulin secretion in the prediabetic group limited to the very early response phase. — Our results strongly support the idea that an impaired ability to secrete insulin under the specific stimulus of the intravenous glucose is a distinguishing feature of the pancreatic beta cell in those humans pre-disposed to diabetes mellitus.

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Untersuchungen zum Prädiabetes. Insulinausschüttung nach oraler Glucosezufuhr und intravenösen Gaben von Tolbutamid und schnell injizierter Glucose bei genetischen Prädiabetikern

Zusammenfassung Die Reaktion von 22 normalgewichtigen genetischen Prädiabetikern, deren beide Elternteile Diabetiker waren, wurde mit der von 34 stoffwechselgesunden Freiwilligen entsprechenden Alters und Gewichtes verglichen. Als standardisierte Stimulationsmethoden dienten: der orale Glucosetoleranztest (100 g Glucose), der i.v. Tolbutamid-Toleranztest (1 g) und die schnelle i.v. Injektion von 0.33 g Glucose/kg Körpergewicht. Die Spiegel des Blutzuckers, des immunreaktiven Insulins und der unveresterten Fettsäuren (NEFA) wurden bei beiden Gruppen im Nüchternzustand und zu verschiedenen Zeiten während der 3 Tests bestimmt.-Die Resultate zeigten keine signifikanten Unterschiede in bezug auf die Kohlenhydrat-Toleranz und das Verhalten der NEFA zu irgend einem Zeitpunkt der benutzten Tests bei Normalpersonen und Prädiabetikern. Bei enger Übereinstimmung der Nüchternspiegel des plasma-immunreaktiven Insulins fanden sich auch keine signifikanten Unterschiede in der Ausschüttung nach oraler Glucosegabe oder i.v. Tolbutamidinjektion. Dagegen ergab sich nach schneller i.v. Glucoseinjektion eine deutlich verringerte Insulinfreisetzung bei der Gruppe der Prädiabetiker, die sich jedoch auf die Frühphase beschränkte. — Unsere Resultate sprechen durchaus dafür, daß eine verringerte Kapazität zur Ihsulinausschüttung nach dem spezifischen Reiz der i.v. Glucosebelastung ein Charakteristikum der Pankreas--Zelle der Menschen darstellt, die zum Diabetes mellitus prädisponiert sind.

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Etude du prédiabète. Réponse de Vinsuline au glucose oral, au tolbutamide intraveineux et à la rapide infusion intraveineuse de glucose chez des sujets génétiquement prédiabétiques

Résumé Vingt-deux sujets non-obèses, génétiquement prédiabétiques (issus de deux parents diabétiques) ont été comparés à 34 sujets normaux de même âge et de même poids, en ce qui concerne leur réponse à trois stimuli standardisés: test de tolérance au glucose oral (avec 100 g de glucose), test de tolérance au tolbutamide intraveineux (1 g) et rapide infusion intraveineuse de glucose (0.33 g/kg de poids corporel). La glycémie, l'insuline immunoréactive et les acides gras non-estérifLés (NEFA) ont été mesurés dans les deux groupes à l'état de jeûne et à différents intervalles de temps au cours de chacun des trois tests.-Les résultats n'ont montré de différence significative ni dans la tolérance aux hydrates de carbone, ni dans le comportement des taux de NEFA entre les sujets normaux et les prédiabétiques, à aucun moment au cours des tests choisis. Les taux à jeun d'insuline plasmatique immunoréactive étaient également étroitement comparables dans les deux groupes; ni la charge orale de glucose, ni l'injection intraveineuse de tolbutamide ne provoquait une libération d'insuline significativement différente chez les sujets normaux et les prédiabétiques. Cependant, la rapide infusion intraveineuse de glucose provoquait une sécrétion d'insuline nettement diminuée dans le groupe prédiabétique qui était plutôt limitée à la phase de réponse très précoce.-Nos résultats confirment fortement l'idée qu'une capacité diminuée à sécréter de l'insuline sous l'influence du stimulus spécifique constitué par la charge brutale de glucose intraveineux est un trait plutôt caractéristique de la cellule bêta pancréatique chez ces sujets qui sont fortement prédisposés au diabète sucré.

     

Early-onset type 2 diabetes in obese white subjects is characterised by a marked defect in beta cell insulin secretion, severe insulin resistance and a lack of response to aerobic exercise training

Aims/hypothesis Early-onset type 2 diabetes is associated with marked visceral obesity and extreme insulin resistance, but its pathogenesis and response to treatment are not completely understood. We studied physical fitness, whole-body and hepatic glucose turnover, and insulin secretion in young obese Irish subjects before and after 3 months of aerobic exercise training. We hypothesised that exercise alone, with stable diet, should improve insulin sensitivity. Materials and methods Anthropometric parameters and maximum volume of oxygen utilisation (VO_2max) were measured in 13 subjects with type 2 diabetes and 18 non-diabetic control subjects, matched for age and BMI. Insulin sensitivity and hepatic glucose turnover were measured using the hyperinsulinaemic–euglycaemic clamp. Insulin secretion was assessed from an OGTT and a modified intravenous glucose tolerance test. Some subjects (seven type 2 diabetic, 14 non-diabetic control subjects) then completed a 12-week supervised aerobic exercise programme. All measurements were repeated on completion of the exercise programme. Results Type 2 diabetic subjects had higher WHR, systolic blood pressure and triacylglycerols than non-diabetic control subjects. They were significantly more insulin-resistant as measured both by the clamp and oral glucose insulin sensitivity. They also displayed marked defects in insulin secretion in response to oral and intravenous glucose challenges. Exercise intervention had no significant effect on whole-body or hepatic insulin sensitivity or insulin secretion. VO_2max increased significantly in the non-diabetic control subjects, but not in the type 2 diabetic subjects after exercise training. Conclusions/interpretation Young obese subjects with type 2 diabetes are severely insulin-resistant with marked loss of beta cell function compared with control subjects matched for age and obesity. Neither group responded metabolically to aerobic exercise intervention. N. Burns and F. M. Finucane contributed equally to this work.     

The effect of dimethylbiguanide on glucose tolerance,serum insulin and growth hormone in obese patients

Zusammenfassung An 16 adipösen Patienten wurden der Glucoseassimilationskoeffizientk _G sowie die radio-immunologisch meßbaren Serumspiegel von Insulin und Wachstumshormon während einer intravenösen Glucosebelastung 1. vor, 2. nach einer Woche und 3. nach 10 Wochen peroraler Behandlung mit 2 × 850 mg Dimethyl-biguanid bestimmt. - Die Patienten wurden nach dem ursprünglichenk _G Wert in 3 Gruppen eingeteilt: Gruppe 1: 7 Patienten,k _G > 1.3. Gruppe 2: 7 Patienten,k _G < 1.3. Gruppe 3: 2 Patienten mit manifestem Diabetes mellitus. — In Gruppe 1 ergab sich keine signifikante Änderung des Mittelwertes vonk _G durch die Biguanidtherapie, die ursprüngliche Hyperinsulinämie nahm nach einer Woche auf die Hälfte ab. In Gruppe 2 kam es nach einer Woche zu einem signifikanten Anstieg von k_G, die Insulinspiegel zeigten hier ein unterschiedliches Verhalten: Bei 4 Patienten wurde eine Senkung, bei 3 Patienten eine Erhöhung beobachtet. In Gruppe 3 fand sich nach einer Woche eine Senkung der Nüchternblutzuckerspiegel sowie eine Senkung der reaktiven Insulinspiegel in der Spätphase. Nach Absetzen des Medikamentes nach 10 Wochen waren in allen 3 Gruppen keine signifikanten Veränderungen gegenüber den Ausgangswerten nachweisbar. Die Mittelwerte der Wachstumshormonspiegel, die insgesamt unter 5 ng/ml blieben, ließen insbesondere in Gruppe 2 eine Abnahme unter Biguanidtherapie erkennen. Auffallend waren zeitliche Veränderungen der Sekretionsdynamik des Insulins, meist im Sinne einer Normalisierung; in 3 Fällen kam es jedoch zu einer Verschiebung des reaktiven Maximums in die Spätphase. — Die Untersuchungen zeigten, daß bei übergewichtigen Patienten ohne manifesten Diabetes mellitus eine gestörte intravenöse Glucosetoleranz durch Dimethylbiguanid normalisiert wird und daß bei Adipösen die Insulin- und Wachstumshormonspiegel meist im Sinne einer Normalisierung beeinflußt werden, wenn auch bei einzelnen Patienten ein gegensätzliches Verhalten gefunden wurde. Es ergaben sich Hinweise dafür, daß die Veränderungen der Insulinspiegel nicht immer allein durch eine periphere Biguanidwirkung verursacht sein dürften. Es ließ sich kein sicherer Langzeiteffekt von Dimethylbiguanid nachweisen, vielmehr erwies sich die aktuelle Konzentration des Pharmakons als stoffwechselwirksam.

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Effet du diméthylbiguanide sur la tolérance au glucose, l'insuline du sérum et l'hormone de croissance chez des malades obèses

Résumé Le coefficient d'assimilation du glucose (k_G), les taux sériques d'insuline immunoréactive (IRI) et l'hormone de croissance (GH) ont été déterminés à l'occasion d'une charge de glucose par voie intra-veineuse chez 16 malades obèses avant traitement, après traitement oral d'une semaine au diméthylbiguanide et après traitement de 10 semaines. -Les malades ont été groupés selon leurs valeurs k_G initiales: groupe 1: 7 malades, k_G > 1.3. -groupe 2: 7 malades, k_G < 1.3. -groupe 3: 2 malades avec diabète établi. -Dans le groupe 1, les valeurs k_G moyennes n'ont montré aucun changement significatif à la suite du traitement au biguanide, tandis que l'hyperinsulinémie initiale était réduite de moitié au

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Presented at the 5th Annual Meeting of the Deutsche Diabetesgesellsehaft, Bonn-Bad Godesberg, May 1970.     

The effect of acarbose on insulin resistance in obese hypertensive subjects with normal glucose tolerance: a randomized controlled study

Aim:  Acarbose, a glucose oxidase inhibitor, delays the absorption of glucose thus reducing post-prandial blood glucose level, haemoglobin A1c (HbA1c) and insulin resistance in patients with diabetes mellitus and in subjects with impaired glucose tolerance. The effect of acarbose in subjects with normal glucose tolerance (NGT) has hitherto not been examined. The aim of the present study was to examine the effect of acarbose in obese hypertensive subjects with NGT.
Methods:  A double-blinded, parallel group study was performed on 56 male subjects with hypertension, body mass index (BMI) 27–35 kg/m², fasting blood glucose ≤ 6 mmol/l and a normal oral glucose tolerance test. Blood pressure, HbA1c, lipid profile and insulin resistance [homeostasis model assessment (HOMA) index] were determined initially and following 24 weeks of acarbose, 150 mg/day or placebo. The primary end point was the change in insulin resistance. Anti-hypertensive treatment and diet were kept constant during the study.
Results:  Insulin resistance decreased in acarbose users but not on placebo. HOMA index declined from 5.36 ± 1.7 to 4.10 ± 1.6 (p = 0.001) on acarbose, the corresponding values on placebo were 5.44 ± 1.9 and 5.53 ± 1.7. A decrease in serum triglyceride values (2.16 ± 0.16 mmol/l to 1.76 ± 0.15 mmol/l, p = 0.02) took place on acarbose with no change on placebo. There was no change in BMI, low-density lipoprotein or high-density lipoprotein values in either group. Blood pressure declined equally in both the groups, probably due to better patient compliance.
Conclusions:  Acarbose may reduce insulin resistance and triglycerides also in obese hypertensive subjects with normal glucose tolerance.     

Plasma insulin and free fatty acids in young people with postprandial glycosuria: Plasma insulin response in the cases with borderline glucose tolerance test

Summary Plasma immunoreactive insulin and free fatty acid (F.F.A.) responses to an oral glucose load were observed in young students with glycosuria and with glucose intolerance of a slight degree. — The groups with a diabetic or a borderline glucose tolerance test (G.T.T.) had a delayed and protracted plasma insulin and F.F.A. response. Both responses were significantly greater than in the control group. The result indicates that a sluggish but high rise and a delayed fall of plasma insulin during the glucose load is characteristic of chemical diabetics and this tendency is seen in the cases with a borderline G.T.T. — The subjects with oxyhyperglycemic G.T.T. also had an initial delay in the insulin response and the peak was distinctly higher than in the control, but the fall was sharp. This suggests that oxyhyperglycemia is one of the preceding states of diabetes. — The subjects with renal glycosuria, in the definition of Lawrence, had a high-normal G.T.T., but their insulin and F.F.A. responses showed no difference from those of the normal.     

Diminution of early insulin response to glucose in subjects with normal but minimally elevated fasting plasma glucose. Evidence for early beta-cell dysfunction.

AIM: Systematic analysis of beta-cell function in Japanese health examinees. METHODS: In 938 Japanese health examinees (627 men and 311 women, mean age and body mass index, 54.0 years and 23.6 kg/m2, respectively), plasma specific insulin was measured at fasting and during a 75-g oral glucose tolerance test. The subjects were stratified into six groups based on fasting plasma glucose < or = 5.1 mmol/l, 5.2-6.0 mmol/l, 6.1-6.9 mmol/l, 7.0-7.8 mmol/l, 7.9-8.7 mmol/l, and > or = 8.8 mmol/l as the 1st, 2nd, 3rd, 4th, 5th and 6th groups, respectively. RESULTS: Distribution of fasting insulin showed a very modest 'inverted U' shape, with the peak in the 5th group. Progressive increase from the 1st toward the 5th group was significant. In contrast, the ratio of change in insulin to change in glucose from 0 to 30 min during the glucose tolerance test was greatest in the 1st group and progressively declined in the groups with higher fasting glycaemia. Difference in the ratio was most striking and highly significant between the 1st and 2nd groups. Distribution of the insulin to glucose ratio of subjects with normal glucose tolerance significantly overlapped with that of untreated patients with diabetes. CONCLUSIONS: In a Japanese population, (i) beta-cell starts to deteriorate during normoglycaemia with a minimal elevation of fasting plasma glucose, and (ii) there are glucose-tolerant subjects with beta-cell dysfunction.     

The behaviour of the serum insulin level in non obese adult diabetics after intravenous glucose,tolbutamide and glucagon

Summary The serum insulin and blood glucose levels after the i.v. administration of three secretion stimuli, namely glucose, tolbutamide and glucagon, were investigated in 10 normal weight patients with maturity-onset diabetes and compared with the levels in a control group. The insulin values were lower in the diabetics than in the normals after each of the three stimuli. Glucose was the most potent in normals and the least potent in diabetics. The behaviour of the serum insulin level after glucose was not uniform in the diabetics; in some patients the rise was either delayed or diphasic. It may be assumed that in maturity-onset diabetes of normal body weight the biosynthesis and release of insulin are impaired by some influence exerted by the main factor, i.e. the glucose metabolism within the -cells of the Langerhans islets.

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Zusammenfassung Bei 10 normal-gewichtigen Patienten mit Alters-Diabetes wurde das Verhalten der Insulinaemie und des Blutzuckers nach i.v. Verabreichung von 3 die Insulinsekretion anregenden Substanzen untersucht: Glukose, Tolbutamid, Glukagon. Die Resultate wurden mit denjenigen der Kontroll-gruppe verglichen. Die Insulinwerte nach der Verabreichung der 3 die Sekretion stimulierenden Substanzen waren bei den Diabetikern niedriger als bei den Normalpersonen. Die Glukose erwies sich als der kraeftigste Reiz bei Nicht-Diabetikern und der schwächste bei den Diabetikern. Das Verhalten der Insulinaemie nach Verabreichung von Glukose war bei den Diabetikern nicht gleichmaessig: bei einer Anzahl von Faellen war das Ansteigen der Insulinaemie verspaetet oder zeitigte ein biphasisches Verhalten. Man darf annehmen, dass die Patienten mit Diabetes des Erwachsenenalters und Normalgewicht eine Veraenderung der Biosynthese und der Insulinfreisetzung unter dem Einfluss des Hauptfaktors, d.h. des Glukosestoffwechsels innerhalb der -Zellen der Langerhans'schen Inseln aufweisen.

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Resumen En 10 enfermos de diabetes madura, de peso normal, se ha estudiado el comportamiento de la insulinemia y de la glicemia después de haberles suministrado i.v. tres substancias estimulantes de la secreción insulínica: glucosa, tolbutamida y glicogón. Los resultados han sido comparados con los que se han obtenido en el grupo de control. Los valores insulínicos observados tras el suministro de las tres substancias estimulantes de la secreción han resultado más bajos en los individuos diabéticos que en los sanos. La glucosa ha resultado el estimulante más poderoso en la secreción de individuos normales y el más débil en los diabéticos. El comportamiento de la insulinemia tras suministro de glucosa no ha sido uniforme en los enfermos de diabetes: en una parte de ellos el aumento de la insulinemia se presentaba retrasado o con una marcha difásica. Se puede suponer que los enfermos con diabetes de la madurez y de peso normal presenten una alteración de la biosíntesis y de la liberación de insulina bajo la influencia del factor principal, es decir, del metabolismo de la glucosa dentro de las células de las islas de Langerhans.

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Resume Les AA. ont étudié 10 sujets avec diabète de la maturité, de poids normal, de point de vue de l'insulinemie et de la glycémie après administration i.v. de trois substances stimulantes la sécretion insulinique: glucose, tolbutamide et glucagone. Les résultats étaient comparés avec ceux obténus dans le groupe de contrôle. Les valeurs insulinémiques observés après l'administration des trois substances stimulates la sécretion étaient inferieurs chez les diabétiques vis à vis aux valeurs observés chez les sujets normaux. Le glucose est resulté le stimulus le plus éfficace sur la sécretion chez les sujets normaux et le moins éfficace chez les diabétiques. Le comportément de l'insulinemie après administration de glucose n'était pas uniforme chez les sujets diabétiques: dans une partie de ceux-ci l'augmentation de l'insulinemie était retardée ou démontrait une allure diphasique. On peut envisager que le sujets avec diabète de la maturité et de poids normal présentent une altération de la biosynthèse et de la libération de insuline sous l'influence du facteur principal c'est à dire du métabolisme du glucose dans les cellules beta des îles de Langerhans.

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Riassunto In 10 pazienti affetti da diabete maturo, di peso normale, è stato studiato il comportamento dell'insulinemia e della glicemia in seguito alla somministrazione i.v. di tre sostanze stimolanti la secrezione insulinica: glucosio, tolbutamide e glucagone. I risultati sono stati confrontati con quelli ottenuti nel gruppo di controllo. I valori insulinici osservati dopo la somministrazione delle tre sostanze stimolanti la secrezione sono risultati inferiori nei diabetici che nei soggetti sani. Il glucosio è risultato il più potente stimolo sulla secrezione nei soggetti normali ed il meno potente nei diabetici. Il comportamento dell'insulinemia dopo somministrazione di glucosio non è stato uniforme nei pazienti diabetici: in una parte dei casi l'aumento dell'insulinemia era ritardato od aveva andamento difasico. Si può supporre che i pazienti con diabete della maturità e di peso normale presentino un'alterazione della biosintesi e della liberazione di insulina sotto l'influenza del fattore principale, cioè del metabolismo del glucosio entro le cellule delle isole di Langerhans.

     

Relationship between body fat mass,carbohydrate tolerance and iri response during glucose infusion in subjects with early diabetes

Summary We have studied the interrelationship of total body fat mass, carbohydrate tolerance and IRI response in 17 non-obese and obese subjects, who were suspected of having early diabetes. We carried out an i.v. glucose infusion test consisting of a priming injection of 0.33 g/kg followed by constant glucose infusion of 12 mg/kg/min in all persons. Total body fat mass was estimated by the tritium dilution method. There was a positive correlation of body fat mass, fasting glucose concentration and blood glucose concentration at 150 min as well as a strong correlation between body fat mass and BG area 60–120 min as parameters of carbohydrate tolerance in all subjects, i.e. the degree of carbohydrate intolerance was directly related to the quantity of total body fat mass. A similar correlation was found when the non-obese and obese groups were analyzed separately. In neither group did total body fat mass correlate with parameters of IRI response. In obese subjects with pathological carbohydrate tolerance, however, a positive correlation of basal IRI concentration and total body fat mass was found. Furthermore, a close relation between basal IRI level and parameters of carbohydrate tolerance could be demonstrated in obese subjects. The present study failed to demonstrate any correlation of parameters of carbohydrate tolerance and glucose-induced IRI response in either group. Thus, the significant relationship between body fat mass and degree of carbohydrate intolerance indicates that total body fat mass plays an important role in the disturbance of blood glucose homeostasis in early diabetes with and without obesity. Investigation performed within the medical research project ‘Diabetes mellitus and disturbances of lipid metabolism’, Ministry of Health, GDR.     

Potentiation of insulin release by glucose in man. I. Quantitative analysis of the enhancement of glucose-induced insulin secretion by pretreatment with glucose in normal subjects.

The effect of repeating a 60 min glucose infusion at a 40 to 70 min interval was investigated after an overnight fast in 14 healthy, non-obese subjects with normal glucose tolerance and normal insulin response to glucose administration. When a hyperglycaemic plateau of around 300 mg/100 ml was induced by the first glucose infusion, the insulin response to a second challenge was enhanced over the range of stimulations used. Both the early and late phase insulin responses were amplified, the enhancement being more marked with higher stimulatory levels of glucose. The blood glucose-insulin dose-response curve became steeper after pretreatment with glucose, the stimulatory threshold level not being altered. These findings suggest that the synergism between the glucose pretreatment, and the insulin releasing effect of glucose, is of multiplicative type, resulting in increase of the maximum effect of the glucose.