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Introduction: Resistant starch (RS) has beneficial effects on postprandial glucose metabolism in both animals and adults. Hitherto, there have been no studies in children of the acute metabolic and hormonal effects of RS-containing meals., Objectives: We aimed to compare serial plasma glucose, insulin, gut hormone, leptin profiles and satiety scores in obese children after meals containing variable amounts of RS., Methods: This was a single blind, non-randomised, crossover study of 20 obese children aged 10-14 years old without comorbidities. Three test meals containing rice (M1), rice cooked with coconut oil (M2), rice cooked in coconut oil with lentils (M3) were given in sequence after a 12-hour fast . Blood samples were analysed for glucose (PG), insulin, leptin, glucagon-like polypeptide (GLP) 1, ghrelin and peptide YY (PYY) at appropriate times between 0 and 180 min., Results: Meal M2 resulted in significantly lower postprandial glucose values compared with meal M1 (maximal incremental glucose, ∆C max , p<0.05; area under the curve, ∆AUC 0-3 , p<0.01) and meal M3 (maximal concentration, C max , p<0.01; ∆C max , p<0.001, and ∆AUC 0-3 p<0.01). M2 also produced lower insulin values compared with M1 (p<0.05). Postprandial ghrelin was significantly higher after M1 compared with M3 (p<0.05). PYY, GLP1 and median satiety scores were not significantly different between the three meals., Conclusion: This study shows that M2, the meal containing RS alone, induced beneficial effects on acute postprandial glucose, insulin and ghrelin concentrations in obese children without diabetes. Acute postprandial satiety scores were not significantly affected by the three meals., Trial Registration Number: SLCTR/2020/007., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Stepwise intensification of insulin treatment to match the progressive decline of endogenous insulin secretion has been shown to be an effective management strategy in type 2 diabetes mellitus (T2DM). The efficacy of initiating and titrating a single bolus dose of insulin glulisine to baseline insulin glargine plus oral hypoglycaemic agents (OHAs) was investigated., Methods: This was a 6-month, parallel-group, randomized, open-label, Phase IV study conducted in the US, UK and Russia. People with T2DM (HbA(1c) 7.5-9.5%) using any basal insulin underwent a 3-month run-in period on insulin glargine titrated to optimize fasting blood glucose (BG) control. Those with HbA(1c) >7.0% were randomized to either continue prior therapy (n = 57) or to add a single dose of insulin glulisine (n = 49) immediately prior to the main meal for a further 3 months. Two different titration algorithms were employed for the bolus dose, targeting 2-h postprandial BG ≤135 mg/dL (≤7.5 mmol/l; Russia and UK) or pre-meal/bedtime BG 100-120 mg/dl (5.5-6.7 mmol/l; US)., Results: HbA(1c) and fasting plasma glucose levels decreased during the run-in period. In the 3 months after randomization, more participants in the basal-plus-bolus group reached HbA(1c) <7.0% than the basal-only control group (22.4 vs. 8.8%; p < 0.05), with significantly greater reduction of HbA(1c) (-0.37 vs. -0.11%; p = 0.0290). Rates of hypoglycaemia and mean weight change were comparable between the treatment groups., Conclusions: In people with T2DM inadequately controlled on basal insulin plus OHAs, adding a single injection of insulin glulisine prior to the main meal significantly improves glucose control without undesired side effects., (© 2011 Blackwell Publishing Ltd.)

Aims: A multinational, randomized, double-blind, two-way crossover trial to compare the pharmacokinetic and pharmacodynamic properties of bolus, subcutaneously administered insulin glulisine (glulisine) and insulin aspart (aspart) in insulin-naÏve, obese subjects with type 2 diabetes., Methods: Thirty subjects [9/21 females/males; mean ± SD age: 60.7 ± 7.7 years; body mass index (BMI): 33.5 ± 3.3 kg/m(2) ; duration of diabetes: 6.8 ± 4.6 years; HbA1c: 7.1 ± 0.8%] were included in the analysis. They fasted overnight and then received a 0.2 U/kg subcutaneous dose of glulisine or aspart 2 min before starting a standardized test meal, 7 days apart, according to a randomization schedule. Blood samples were taken every 15 min, starting 20 min before the meal and ending 6 h postprandially., Results: The area under the absolute glucose concentration-time curve between 0 and 1 h after insulin injection and maximal glucose concentration was significantly lower with glulisine than with aspart (p = 0.0455 and 0.0337, respectively). However, for the total study period, plasma glucose concentration was similar for glulisine and aspart. Peak insulin concentration was significantly higher for glulisine than for insulin aspart (p < 0.0001). Hypoglycaemic events (≤ 70 mg/dl with or without symptoms) occurred in 13 and 16 subjects treated with glulisine and aspart, respectively, but there were no cases of severe hypoglycaemia requiring intervention., Conclusions: Glulisine was associated with lower glucose levels during the first hour after a standard meal; the remaining glucose profiles were otherwise equivalent, with higher insulin levels observed throughout the study period., (© 2011 Blackwell Publishing Ltd.)

Aim: This study examined the effects of reductions to pre-exercise rapid-acting insulin dose on changes in blood beta-hydroxybutyrate, glucose, acid-base balance and counter-regulatory hormone responses to prolonged running in individuals with Type 1 diabetes., Methods: Following ethical approval, seven participants with Type 1 diabetes (34±2 years, BMI 27±1 kg/m(2) ) completed this study. After preliminary testing, participants attended the laboratory four times, each time consuming a 1.12 MJ meal (60 g carbohydrate, 2 g fat, 2 g protein), with randomized amounts of their rapid-acting insulin: Full dose (mean 7.3±0.2 units), 75% dose (mean 5.4±0.1 units), 50% dose (mean 3.7±0.1 units) or 25% dose (mean 1.8±0.1 units). After 2-h rest, participants completed 45 min running at 70±1% peak rate of oxygen consumption (VO(2peak) ). Blood metabolites and hormones were recorded over the 2-h rest and 3-h recovery. Data were analysed using repeated-measures ANOVA., Results:   Serum insulin peaked at 60 min in all conditions and was lowest after 25% insulin dose compared with full dose (P=0.03). After the 25% insulin dose immediately pre-exercise glucose concentration was higher than after the full or 50% dose (P<0.05). Resting beta-hydroxybutyrate gradually decreased during 2-h rest (P<0.05) with a similar post-exercise peak of beta-hydroxybutyrate at 3 h (P>0.05). Post-exercise blood pH increased for 5 min to a similar extent with all insulin doses , but the rise with the 25% dose was less compared with the full dose (P=0.01). Blood lactate and plasma catecholamines increased after running similarly with all insulin reduction conditions (P<0.05). Blood glucose area under the curve (BG(auc) ) after the 25% insulin dose was greater than after the 75% dose (P=0.02)., Conclusion: Ketogenesis following running was not influenced by reductions in pre-exercise rapid-acting insulin dose. This important preparatory strategy aids preservation of blood glucose but poses no greater risk to exercise-induced ketone body formation., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

In this study, we examined the glycaemic and fuel oxidation responses to alterations in the timing of a low glycaemic index carbohydrate and 75% reduced insulin dose, prior to running, in type 1 diabetes individuals. After carbohydrate (75 g isomaltulose) and insulin administration, the seven participants rested for 30 min, 60 min, 90 min or 120 min (conditions 30MIN, 60MIN, 90MIN, and 120MIN, respectively) before completing 45 min of running at 70% peak oxygen uptake. Carbohydrate and lipid oxidation rates were monitored during exercise and blood glucose and insulin were measured before and for 3 h after exercise. Data were analysed using repeated-measures analysis of variance. Pre-exercise blood glucose concentrations were lower for 30MIN compared with 120MIN (P < 0.05), but insulin concentrations were similar. Exercising carbohydrate and lipid oxidation rates were lower and greater, respectively, for 30MIN compared with 120MIN (P < 0.05). The drop in blood glucose during exercise was less for 30MIN (3.7 mmol · l(-1), s(x) = 0.4) compared with 120MIN (6.4 mmol · l(-1), s(x) = 0.3) (P = 0.02). For 60 min post-exercise, blood glucose concentrations were higher for 30MIN compared with 120MIN (P < 0.05). There were no cases of hypoglycaemia in the 30MIN condition, one case in the 60MIN condition, two in the 90MIN condition, and five in the 120MIN condition. In conclusion, a low glycaemic index carbohydrate and reduced insulin dose administered 30 min before running improves pre- and post-exercise blood glucose responses in type 1 diabetes.

Aim: Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin)., Methods: Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m(2), haemoglobin A(1c) (HbA(1c)) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days., Results: Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280-330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC(0-6 h) (910 +/- 270 vs. 472 +/- 245 pmol h/L; 950 +/- 446 vs. 433 +/- 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA(1c), weight and triglycerides were observed., Conclusions: Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations.

A comparison of the plasma glucose and insulin day profiles between two prandial rapid-acting insulin analogues, insulin glulisine (glulisine) and insulin lispro (lispro), in 18 obese subjects with Type 2 diabetes. Subjects (body mass index: males, 36.7 [33.2-43.8] kg/m(2); females, 40.0 [35.7-46.5] kg/m(2)) received subcutaneous glulisine or lispro (0.15 U/kg) at 4-h intervals immediately (within 2 min) before three standard test meals during each of two 12-h, randomised, open-label, crossover studies (7+/-2-day interval between each). Overall, preprandial-subtracted glucose concentrations (area under the curve) were similar on the glulisine and lispro study days. However, the mean of the three maximal preprandial subtracted plasma glucose concentrations (DeltaGLU(max)) were lower with glulisine versus lispro (12%; p<0.01). Mean concentrations of insulin analogue were significantly higher post-meal with glulisine (p<0.01 for all). Post hoc analysis showed a significantly faster absorption rate for glulisine versus lispro in the first 30 min post-meal (estimated difference 0.48 microU/min; p<0.0001). Only two cases of hypoglycaemia were reported; both from one subject during the lispro day. When glulisine is injected immediately before a meal in obese patients with Type 2 diabetes, glulisine achieves significantly lower glucose excursions over lispro. Significantly faster absorption with higher and sustained post-meal levels of insulin analogue was achieved at every meal with glulisine versus lispro.

Objective: To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 +/- 10 years, BMI 22.4 +/- 1.6 kg/m2, and A1C 7.2 +/- 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study)., Research Design and Methods: Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was >150 mg/dl)., Results: With glargine, plasma glucose remained at 103 +/- 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose <180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P < 0.001). Estimated total insulin activity (GIR area under the curve [AUC](0-end of GIR)) was 1,412 +/- 662 and 915 +/- 225 mg/kg (glargine vs. detemir, P < 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P < 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids(0-24 h) 11 +/- 1.7 vs. 8 +/- 2.8 mmol/l, respectively, P < 0.001)., Conclusions: Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12-24 h.

Aims/hypothesis: The pharmacokinetic and pharmacodynamic properties of biphasic insulin aspart (BIAsp 30) (30% soluble, 70% protaminated insulin aspart [IAsp]) and insulin glargine (IGlarg) were compared., Methods: Twelve people with type 2 diabetes took part in two 24-h isoglycaemic clamp studies, 1 week apart. Patients were randomised to treatment with 0.5 U/kg of BIAsp 30 (0.25 U/kg at 08.30 h and 0.25 U/kg at 20.30 h) or 0.50 U/kg IGlarg at 08.30 h. Both insulins were given by subcutaneous injection into the anterior abdominal wall. The plasma glucose, glucose infusion rates, plasma insulin and C-peptide concentrations were measured., Results: All 12 patients were men; mean (+/-SD) age was 58.8 (8.9) years, BMI 31.0 (3.0) kg/m2 and HbA(1c) 7.1 (0.6)%. Plasma glucose was constant throughout the 24-h clamp period. After each injection of BIAsp 30, glucose infusion rates increased, reaching a distinct peak approximately 3-5 h after injection. A much flatter postinjection profile was observed following IGlarg administration. Plasma insulin concentrations rose rapidly after each injection of BIAsp 30, reaching a distinct peak after approximately 2-3 h. A flatter plasma insulin profile reached a plateau approximately 6-16 h after IGlarg administration. Plasma C-peptide fell below baseline after both injections of BIAsp 30 but remained unaltered after IGlarg injection., Conclusions/interpretation: The pharmacodynamic and pharmacokinetic profiles were 34 and 28%, respectively, higher following equivalent doses (0.5 U/kg) of BIAsp 30 given as two split doses than following IGlarg given as a single daily dose.

The aim of this study was to compare the subcutaneous absorption characteristics of insulin glargine with NPH insulin in patients with Type 2 diabetes. In this single-dose, double-blind, randomized, two-way crossover study, 14 patients with Type 2 diabetes (aged 40-70 years) previously untreated with insulin were randomized to receive in a fasting state either a single subcutaneous injection of 0.3 U/kg 125I-insulin glargine or 0.3 U/kg 125I-NPH insulin. The disappearance of radioactivity was monitored for forty-eight hours. The median time for 25%, 50% and 75% of the radioactivity to disappear from the injection site was significantly longer for insulin glargine compared with NPH insulin (T75% 15.0 and 6.5 h, p=0.009; T50% 26.3 and 13.4 h, p=0.009; T25% 42.4 and 26.6 h, p=0.019, respectively). The mean residual radioactivity remaining at 24, 36 and 48 h after injection remained significantly higher than NPH insulin (54.4 and 27.9%, p=0.0001; 35.0 and 17.0%, p=0.003; 19.2 and 9.2%, p=0.01, respectively). Mean plasma glucose levels reached a minimum after 14.6 and 9 h in response to insulin glargine and NPH insulin, respectively. The subcutaneous absorption of insulin glargine in fasting Type 2 diabetes patients was significantly (2-3 times) slower compared with NPH insulin in patients with Type 2 diabetes. The slower absorption of insulin glargine correlated with the fall in plasma glucose levels over a 24 h period compared with the faster insulin absorption and more rapid decrease in plasma glucose levels observed in response to NPH insulin. Both insulin glargine and NPH insulin were well tolerated.

The major contributory factor to increasing hyperglycaemia in established Type 2 diabetes mellitus (T2DM) appears to be the progressive delay and attenuation of the prandial insulin response. An important consequence of this derangement is that hepatic glucose production is no longer suppressed during times of prandial glucose intake. Together with a relative impairment in the rate of peripheral glucose disposal, this leads to supra-physiological plasma glucose excursions, which may damage the vasculature. An obvious therapeutic strategy, therefore, would be to increase insulin availability when most needed--in the early prandial phase. In experiments with exogenous insulin interventions, peak post-prandial blood glucose increments were curtailed without undue increases in total insulin exposure. However, available evidence suggests that the sulphonylurea glibenclamide does not effectively alter early-phase prandial insulin release but predominately increases late-phase and basal insulin output, thus incurring the risk of hypoglycaemia. The novel insulin secretagogue repaglinide, by contrast, augments early-phase prandial insulin secretion when taken before meals, as shown by studies in non-diabetic people and patients with newly diagnosed, previously untreated T2DM. Repaglinide exerts its greatest effect on the insulin secretion rate during the first 30 min after a meal is started, thereby going some way to restoring the early insulin secretion curve seen after a meal in non-diabetic people. No residual secretagogue activity is seen 4 hr after taking a single dose of up to 2 mg. Prandial glucose regulation with repaglinide could be associated with lower post-prandial glucose excursions and less risk of post-prandial hypoglycaemia than glibenclamide.

Aims: beta-cell responsiveness was related to fasting plasma glucose to gain further understanding of pathophysiology of Type 2 diabetes., Methods: An insulin secretion model gave fasting beta-cell responsiveness M0 (ability of fasting glucose to stimulate beta-cell) and postprandial beta-cell responsiveness MI (ability of postprandial glucose to stimulate beta-cell) by analysing glucose and C-peptide time-concentration curves sampled every 10-30 min over 240 min during a meal tolerance test (MTT; 75 g CHO, 500 kcal). Caucasian subjects with newly presenting Type 2 diabetes according to WHO criteria (N = 83, male/female: 65 : 18, age: 54 +/- 10 years, body mass index (BMI): 30.9 +/- 5.2 kg/m2, fasting plasma glucose (FPG): 11.0 +/- 3.2 mmol/L; mean +/- SD) and Caucasian healthy subjects (N = 54, m/f: 21 : 33, age: 48 +/- 9 years, BMI: 26.1 +/- 3.7 kg/m2, FPG: 5.1 +/- 0.4 mmol/L) were studied., Results: A continuum inverse relationship between MI and FPG was observed. In the diabetes group, MI was closely related to FPG (rs = -0.74, P < 0.0001) and explained 60% intersubject FPG variability with the use of an exponential regression model., Conclusions: In newly presenting Type 2 diabetes in Caucasian subjects a close inverse association exists between postprandial beta-cell responsiveness and FPG.

Objective: To determine the subcutaneous absorption rates and the appearance in plasma of 3 formulations of the long-acting human insulin analog insulin glargine (HOE 901) differing only in zinc content (15, 30, and 80 microg/ml)., Research Design and Methods: We conducted 2 studies. Study 1 compared the subcutaneous abdominal injection of 0.15 U/kg of 125I-labeled insulin glargine[15], insulin glargine[80], NPH insulin, and placebo. In study 2, 0.2 U/kg of insulin glargine[30] was injected into the arm, leg, and abdominal regions. Both studies had a randomized crossover design; each enrolled 12 healthy men, aged 18-50 years., Results: In study 1, the time in hours for 25% of the administered radioactivity to disappear after bolus subcutaneous injection (T75%) for NPH insulin indicated a significantly faster absorption rate compared with the 2 insulin glargine formulations (3.2 vs. 8.8 and 11.0 h, respectively P < 0.0001). Mean residual radioactivity with NPH insulin was also significantly lower at 24 h (21.9 vs. 43.8 and 52.2%, P < 0.0001). The calculated plasma exogenous insulin concentrations after NPH insulin were substantially higher than those with insulin glargine, reaching a peak within the first 6 h after administration before declining. Insulin glargine, however, did not exhibit a distinct peak. Weighted average plasma glucose concentration between 0 and 6 h was significantly lower after NPH compared with insulin glargine (P < 0.001). In study 2, there were no significant differences in the absorption characteristics of insulin glargine between the 3 injection sites (T75% = 11.9, 15.3, and 13.2 h for arm, leg, and abdomen, respectively) or in residual radioactivity at 24 h., Conclusions: Subcutaneous absorption of insulin glargine is delayed compared with NPH insulin. There is little or no difference in the absorption rate of insulin glargine between the main subcutaneous injection sites.

Objective: To examine the dose-related pharmacodynamics and pharmacokinetics of a single preprandial oral dose of repaglinide in patients with type 2 diabetes., Research Design and Methods: A total of 16 Caucasian men with type 2 diabetes participated in two placebo-controlled double-blind randomized cross-over studies. Patients were randomized to receive a single oral dose of repaglinide (0.5, 1.0, and 2.0 mg in study 1 and 4.0 mg in study 2) or placebo (both studies) administered 15 min before the first of two sequential identical standard meals (breakfast and lunch) that were 4 h apart. During each of the study days, which were 1 week apart, blood samples were taken at frequent intervals over a period of approximately 8 h for measurement of plasma glucose, insulin, C-peptide, and repaglinide concentrations., Results: During the first meal period (0-240 min), administration of repaglinide reduced significantly the area under the curve (AUC) for glucose concentration and significantly increased the AUC for insulin levels, C-peptide levels, and the insulin secretion rate. These results, compared with those of administering placebo, were dose dependent and log linear. The effect of repaglinide administration on insulin secretion was most pronounced in the early prandial period. Within 30 min, it caused a relative increase in insulin secretion of up to 150%. During the second meal period (240-480 min), there was no difference between repaglinide and placebo administration in the AUC for glucose concentration, C-peptide concentration, and the estimated insulin secretion rate., Conclusions: A single dose of repaglinide (0.5-4.0 mg) before breakfast improves insulin secretion and reduces prandial hyperglycemia dose-dependently Administration of repaglinide had no effect on insulin secretion with the second meal, which was consumed 4 h after breakfast.

Beta-cell secretion and insulin sensitivity was studied in healthy subjects and newly diagnosed Caucasian (Welsh) NIDDM patients. A standardized meal tolerance test (MTT) and frequent sampled intravenous glucose tolerance tests (FSIVGTT) were employed and the patients stratified according to fasting plasma glucose (FPG). A deficient early (first hour) post-prandial (MTT) insulin secretion was demonstrated in all NIDDM patients, deteriorating with increasing fasting hyperglycaemia. For the patient group fasting and post-prandial hyperproinsulinaemia was evident with diminishing post-prandial excursions as fasting hyperglycaemia increased. The early phase (0-10 min) insulin secretion to intravenous glucose (300 mg kg-1) was severely impaired in NIDDM patients. A shortlived paradoxical fall in plasma insulin concentrations was observed in those with FPG > 9 mmol l-1. Insulin sensitivity utilizing the insulin modified FSIVGTT demonstrated that all NIDDM patients had marked insulin insensitivity. Characteristic of the newly diagnosed previously untreated Caucasian NIDDM is a dysfunctional beta cell, resulting in a deficit in insulin secretion with relative hyperproinsulinaemia. The quantitative and qualitative secretory status of the beta cell decreases with increasing fasting hyperglycaemia. Insulin sensitivity is markedly reduced when FPG exceeds 7.0 mmol l-1 with little or no further discernible fall with deteriorating glycaemic control.

A new guar-containing wheatflake product was developed to assess its effect on carbohydrate tolerance in normal-weight, healthy subjects. The extruded wheatflake breakfast cereals containing 0 (control) or approximately 90 g guar gum/kg DM were fed to ten fasting, normal-weight, healthy subjects using a repeated measures design. The meals were similar in energy (approximately 1.8 MJ), available carbohydrate (78 g), protein (15 g) and fat (5.4 g) content. The guar gum content of the test meals was 6.3 g. Venous blood samples were taken fasting and at 15, 30, 45, 60, 90, 120, 150 and 240 min after commencing each breakfast and analysed for plasma glucose, insulin and C-peptide. The guar wheatflake meal produced a significant main effect for glucose and insulin at 0-60 min and 0-240 min time intervals respectively, but not for the C-peptide levels compared with the control meal. Significant reductions in postprandial glucose and insulin responses were seen following the guar wheatflake meal compared with the control meal at 15 and 60 min (glucose) and 15, 60, 90 and 120 min (insulin). The 60 and 120 min areas under the curve for glucose and insulin were significantly reduced by the guar gum meal, as was the 240 min area under the curve for insulin. Thus, it can be concluded that the use of a severe method of heat extrusion to produce guar wheatflakes does not diminish the physiological activity of the guar gum.

Minimal model (MINMOD) analysis of the frequently sampled intravenous glucose tolerance test (FSIVGTT) is dependent on an adequate insulin response to the glucose load. As this is characteristically deficient in subjects with non-insulin-dependent diabetes mellitus (NIDDM), the technique has been modified by the use of an intravenous bolus of insulin. Previous validation of this modification in humans has relied on agreement between insulin sensitivity indexes (SI) estimated from tolbutamide- and insulin-modified tests and not on direct comparison with estimates derived from the isoglycemic glucose clamp. We have compared estimates of insulin sensitivity derived from minimal modeling of a 4-h insulin-modified FSIVGTT and the glucose clamp in subjects with NIDDM. Twelve subjects underwent an insulin-modified FSIVGTT and an isoglycemic hyperinsulinemic clamp in random order 2-4 weeks apart. Fasting plasma glucose (8.4 vs. 9.0 mmol/l) and immunoreactive insulin (IRI) concentrations (104.5 vs. 101.5 pmol/l) were not different between the 2 study days. SI(clamp) was derived from the steady-state glucose infusion rate during the 3rd h of the clamp, corrected for the ambient insulin and glucose concentrations. SI(ivgtt) was derived using MINMOD. SI(ivgtt) was 1.06 +/- 0.18 min-1.mU-1.ml x 10(4), and mean SI(clamp) was 4.97 +/- 0.69 l.min-1/pmol.l-1 x 10(4) (mean +/- SE). SI(ivgtt) was positively correlated with SI(clamp) (r = 0.73, P = 0.004) and negatively correlated with body mass index (r = -0.7, P = 0.005) and fasting IRI(ivgtt) (r = -0.64, P = 0.008). In summary, MINMOD analysis of the insulin-modified FSIVGTT provides a valid measure of insulin sensitivity in subjects with NIDDM.

In both fasting normal and diabetic subjects, nasally administered insulin achieves significant falls in plasma glucose concentrations. Repeated administration before and during a meal has been necessary to lower postprandial glycaemic excursion in subjects with NIDDM. We have studied the use of Novolin Nasal which employs a non-irritant, lecithin-based enhancer as a vehicle for human insulin, on postprandial glucose profiles in NIDDM subjects to determine efficacy, optimal dose frequency, and tolerability. Seventeen NIDDM subjects (15 men, 2 women) participated in a randomized, partially blinded, placebo-controlled, crossover trial of three active treatment regimens (nasal insulin, 120 U at 0 min, 60 U at 0 and +20 min or 120 U at +20 min) in relation to a standardized mixed meal given at 0 min. All active treatments significantly reduced postprandial glucose concentrations compared to placebo. Intranasal insulin given at 0 min at a dose of 60 U or 120 U resulted in a 50% reduction in postprandial incremental glucose compared to placebo over the first 2 h, whereas treatment with 60 U both at 0 and 20 min lead to a 70% reduction over the 240 min postprandial period. Post-prandial intravenous insulin was the least effective. There were no episodes of symptomatic hypoglycaemia. Local tolerability was excellent with only four reports of transient nasal irritation out of a total of 68 doses. The delivery device was accurate with intra-device CV of delivered dose of 4.8%.(ABSTRACT TRUNCATED AT 250 WORDS)

The reported glucose and immunoreactive insulin (IRI) responses to oral and intravenous glucose in subjects with Type 2 diabetes have not always been consistent. This may have resulted from variations in the method of glucose administration, the ethnic backgrounds of subjects, the diagnostic criteria applied, the duration of the disease or IRI assay methods. The use of a mixed meal rather than glucose has been shown to provide a more physiological stimulus to the pancreatic beta-cell due to both glucose and non-glucose secretagogues. We have analysed the metabolic and hormonal responses of 188 newly diagnosed Caucasian subjects with Type 2 diabetes and 38 non-diabetic subjects to a 500 kcal mixed meal. The diabetic subjects were stratified according to fasting plasma glucose (FPG) (< 9, 9-12, 12-15 and > or = 15 mmol/l) and body mass index (BMI) (< 26.5, 26.5-30 and > or = 30 kg/m2). Increasing FPG was associated with higher peak glucose concentrations and increasing failure to achieve basal glucose levels by 4 h. Median fasting IRI concentrations were similar to those of normal subjects, but all diabetic subjects had reduced early-phase insulin secretion. Diabetic subjects with FPG < 9 mmol/l showed augmented IRI area under the curve (AUC) at 2 and 4 h, whereas those with FPG > 9 mmol/l had progressive falls in IRI AUC to below that of the normal subjects (P < 0.0001 for the trend). Peak IRI concentrations declined progressively with increasing FPG. Despite equivalent glucose exposure simple trends of increasing AUC, IRI with increasing BMI were statistically significant (P < 0.001, P < 0.02, P < 0.001 and P < 0.01, respectively for each FPG group). Both fasting and AUC non-esterified fatty acid concentrations increased significantly with FPG regardless of BMI (P < 0.001 for the trends). These results using a more physiological mixed meal challenge in a large number of recently diagnosed Type 2 diabetic subjects demonstrate a marked and increasing loss of beta-cell secretory function with increasing fasting hyperglycaemia aggravated by insulin resistance with increasing obesity.

An intravenous glucose tolerance test (IVGTT) glucose dose of 0.3 g/kg has been adopted for measurement of insulin sensitivity using the minimal model. Traditionally, however, a dose of 0.5 g/kg has been used, which might be expected to improve the IVGTT insulin response and hence the effectiveness of minimal model analysis. In a preliminary study of 5 subjects given 0.3 and 0.5 g/kg IVGTTs, each lasting 120 minutes, we found a 53% increase in IVGTT insulin response at the higher dose, but there was a marked discrepancy in the difference between fasting and final glucose concentrations (-0.17 mmol.l-1 at 0.3 g/kg and -1.01 mmol.l-1 at 0.5 g/kg). Good agreement obtained between estimates of Si derived from 0.3 and 0.5 g/kg IVGTTs (mean Si: 0.3 g/kg test = 6.0 min-1.microU-1.ml, 0.5 g/kg test = 5.8 min-1.microU-1.ml: r = 0.97, p < 0.001) providing the final IVGTT glucose concentration rather than the fasting concentration was taken as the basal level for modelling analysis. These findings were confirmed and extended in two further studies; firstly in an analysis of the effects of choice of basal glucose concentration and the application of various modelling constraints in a cross-section of 66 subjects with a wide range of insulin sensitivities; then in a further study in which seven subjects were each given two 0.3 g/kg IVGTTs and one 0.5 g/kg IVGTT, with each test being prolonged to 300 minutes. Agreement between estimates of Si at the two different doses was again only achieved by taking the final IVGTT glucose concentration as basal (mean Si: 0.3 g/kg test = 4.7 min-1.microU-1.ml, 0.5 g/kg test = 3.8 min-1.microU-1.ml: r = 0.75, p < 0.05), although one anomalous test required that a constraint be applied to the modelling process for this agreement to obtain. Closest agreement between the 300 minute 0.3 and 0.5 g/kg IVGTTs was found when tests were modelled up to 180 minutes. An IVGTT duration of 180 minutes appears to be optimum for re-establishing the basal concentration necessary for effective modelling analysis. Application of constraints can markedly affect certain analyses and may introduce some bias; their use should be carefully monitored, although their effect on large datasets is likely to be small.

Diabetes mellitus is a chronic state of excessive blood glucose levels (hyperglycaemia), which may result from many environmental and genetic factors, often acting jointly. The major regulator of glucose concentration in the blood is insulin. It is known that about 50% of the insulin is taken up by the liver on passing through it after secretion from the pancreas. The precise value of this fractional uptake is not known, so the prehepatic insulin secretion rates cannot be readily estimated from the plasma insulin concentration levels. By utilizing the equimolar secretion of insulin and connecting peptide (C-peptide) from the pancreas, a noninvasive method has been formulated. This was based on a compartmental model which involved the pancreas, liver, and plasma. The resulting differential equation yielded a gamma variate solution which could be readily linearized. The model was then tested on 56 normal (51 nonobese and 5 obese) subjects, and three groups of subjects with diabetes who could be labelled as mild, moderate, and severe (based on the fasting plasma glucose concentration) with 83, 88, and 64 subjects respectively. We have focused on the human patient environment of the clinician to produce a distinct model which gave a consistent pattern within all four groups with good fits between observed and theoretical values of the plasma insulin levels. The consequent rates for insulin secretion were consistent across the groups and were clinically meaningful.

Recent work in healthy subjects, the aged, and subjects with gestational diabetes or drug-induced insulin resistance using minimal model analysis of the tolbutamide-modified frequently sampled intravenous glucose tolerance test suggested that a reduced sampling regimen of 12 time points produced unbiased and generally acceptable estimates of insulin sensitivity (SI) and glucose effectiveness (SG) compared with a full sampling schedule of 30 time points. We have used data from 26 insulin-modified frequently sampled intravenous glucose tolerance tests in 21 subjects with NIDDM to derive and compare estimates of SI and SG from the full sampling schedule (SI(30), SG(30)) with those estimated from the suggested 12 time points (SI(12), SG(12)) and those estimated with the addition of a 25-min time point (SI(13), SG(13)). Percentage relative errors were calculated relative to the corresponding 30 time-point values. A statistically significant bias of 15% (97% confidence interval from 7.4 to 25.6%, interquartile range 25%) was introduced by the estimation of SI(12) but not SI(13) (1%, 97% confidence interval from -9.4 to 9.3%, interquartile range 21%). Results for SG(12) (-12%, 97% confidence interval from -46.7 to 1.2%, interquartile range 49%) and SG(13) (-5%, 97% confidence interval from -27.8 to 6.8%, interquartile range 37%) were statistically equivocal. The precision of estimation of SI(12), SG(12), and SG(13) measured by the interquartile range of the percentage relative errors was poor. The precision of determination measured by the median minimal model coefficient of variation was 18, 29, and 27% for SI(30), SI(12), and SI(13) and 9, 11, and 11% for SG(30), SG(12), and SG(13), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

In NIDDM patients the deficient initial rise in insulin is a consistent finding. This early phase of insulin secretion influences the degree of hyperglycaemia following a meal. In this study insulin was infused intravenously into newly diagnosed NIDDM patients in an attempt to mimic the non-diabetic insulin response to a mixed meal and to determine the effect of early insulin availability on post-prandial glucose, C-peptide and insulin concentrations in NIDDM patients. The study involved standardized meal tolerance tests (MTT) with and without insulin on 2 separate days, 1 week apart. Insulin was given by intravenous infusion (2.5 U Actrapid over 30 min) immediately following the start of a 500 kcal MTT. The subjects were divided into non-obese and obese sub-groups with 8 subjects in each group (BMI 24.0 vs 32.0 kg/m2, HbA1, 12.7 vs 9.8%, age 44.4 vs 43.0 yrs, respectively). Following intravenous insulin in non-obese diabetics a peak plasma insulin concentration of 0.393 pmol/ml was observed at 15 min compared to 0.148 pmol/ml at 90 min without exogenous insulin. The post-prandial glucose excursion between 60 and 120 min was significantly lowered with insulin (p less than 0.01). Similarly in the obese patients a higher and earlier insulin peak was achieved with intravenous insulin, with a lower level during the second half of the 4 h post-prandial period, the difference reaching significance at 150 min (p less than 0.05). No differences were observed in the C-peptide concentrations between the 2 study days.(ABSTRACT TRUNCATED AT 250 WORDS)

A cohort of 132 well-documented White Welsh non-insulin-dependent diabetic (NIDDM) subjects were genotyped for 5 restriction-fragment-length polymorphisms (RFLPs) at the insulin-receptor gene (IRG) locus and a polymorphic locus 5' to the insulin gene. There was no significant difference in RFLP frequencies between the NIDDM subjects and a group of 87 matched White control subjects. Paired haplotype analysis of the IRG RFLPs suggested a difference between NIDDM and control groups for the endonuclease combinations Bgl II-Rsa I and Bgl II-Xba I. Analysis of implied haplotypes defined by the endonucleases Bgl II, Rsa I, and Xba I revealed one haplotype to be more prevalent in the NIDDM group; whereas, another haplotype was associated with the control group (P less than 0.02). Subset analysis within the NIDDM cohort compared the metabolic response of NIDDM subjects with the differing IRG haplotypes to a standard meal tolerance test. Both groups showed equivalent basal and postprandial glucose excursions, but one group revealed a significantly exaggerated plasma insulin response compared with the other (P less than 0.05). This may reflect the influence of genetic variation at the IRG locus on insulin sensitivity in patients with NIDDM.

The effects of an intravenous infusion of porcine GIP on beta-cell secretion in patients with untreated type 2 diabetes mellitus have been studied. The subjects were studied on two separate days. After a 10 h overnight fast and a further 120 min basal period they were given an intravenous infusion of porcine GIP (2 pmol.kg-1.min-1) or control solution in random order from 120-140 min. Frequent plasma glucose, insulin, C-peptide and GIP measurements were made throughout and the study was continued until 200 min. Plasma glucose levels were similar throughout both tests. During the GIP infusion there was an early significant rise in insulin concentration from 0.058 +/- 0.006 nmol/l to 0.106 +/- 0.007 nmol/l (P less than 0.01) within 6 min of commencing the GIP infusion and insulin levels reached a peak of 0.131 +/- 0.011 nmol/l at 10 min (P less than 0.01). Insulin levels remained significantly elevated during the rest of the GIP infusion (P less than 0.01-0.001) and returned to basal values 20 min post infusion. No change in basal insulin values was seen during the control infusion. C-peptide levels were similarly raised during the GIP infusion and the increase was significant just 4 min after commencing the GIP infusion (P less than 0.05). GIP levels increased from 16 +/- 3 pmol/l prior to the infusion to a peak of 286 +/- 24 pmol/l 20 min later. At 4 min when a significant beta-cell response was observed GIP levels were well within the physiological range.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraperitoneal absorption of human insulin (crb) and porcine insulin was examined in 9 diabetic patients with renal failure, and on Continuous Ambulatory Peritoneal Dialysis (CAPD). Serial blood sampling was performed to determine the characteristics of insulin absorption and glycaemic control. Four patients received successive equal doses of human and porcine insulins, 2 received different doses and 3 received human insulin only. Glycaemic control was similar after both insulins. Mean insulin levels were consistently higher after human insulin with significant differences at 90, 300 and 360 min. It is concluded that, if required, patients may be transferred from i.p. purified porcine to i.p. human insulin without a change in insulin dose.

The effects of porcine glucose-dependent insulinotropic polypeptide given by continuous intravenous infusion in normal subjects (n = 6) and Type 2 (non-insulin-dependent) diabetic patients (n = 6) have been investigated. The subjects were studied on 2 separate days after overnight fasts. On each day 25 g of glucose was infused from 0-30 min plus an infusion of either porcine glucose-dependent insulinotropic polypeptide (0.75 pmol . kg-1 . min-1) or control solution. During the glucose-dependent insulinotropic polypeptide infusion plasma glucose values were reduced in normal subjects from 30-60 min (p less than 0.01) and in Type 2 diabetic patients at 45 and 60 min (p less than 0.05). In the normal subjects insulin concentrations were greater from 10-35 min (p less than 0.01) following glucose-dependent insulinotropic polypeptide infusion and peak values were increased by 123%. In the Type 2 diabetic patients following glucose-dependent insulinotropic polypeptide infusion insulin levels were increased from 4-40 min (p less than 0.01) but peak values were only increased by 27%. In the normal subjects C-peptide values were greater from 25-45 min (p less than 0.01) following glucose-dependent insulinotropic polypeptide infusion and peak C-peptide levels were increased by 82%. In the Type 2 diabetic patients following the glucose-dependent insulinotropic polypeptide infusion C-peptide levels were increased from 6-55 min (p less than 0.01) and peak values were increased by 20%. Plasma glucose-dependent insulinotropic polypeptide levels were within the physiological post prandial range during the glucose-dependent insulinotropic polypeptide infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Considerable disagreement exists regarding the levels of immunoreactive glucose dependent insulinotropic polypeptide in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Glucose dependent insulinotropic polypeptide levels were therefore studied during oral glucose and mixed meal tolerance tests in normal subjects (n = 31) and newly presenting previously untreated patients with Type 2 diabetes mellitus (n = 68). The tests were performed in random order after overnight fasts and blood samples were taken at 30 min intervals for 4 h. During the oral glucose tolerance test plasma glucose dependent insulinotropic polypeptide levels increased in the normal subjects from a fasting value of 20 +/- 3 pmol/l to a peak of 68 +/- 5 pmol/l at 30 min and in the Type 2 diabetic patients from a similar fasting level of 27 +/- 3 pmol/l to a higher peak value of 104 +/- 6 pmol/l at 30 min (p less than 0.001). Glucose dependent insulinotropic polypeptide levels were significantly higher in the diabetic patients compared with the normal subjects from 30-90 min (p less than 0.01-0.001) following oral glucose. During the meal tolerance test glucose dependent insulinotropic polypeptide levels increased in the normal subjects from a pre-prandial value of 22 +/- 4 pmol/l to a peak of 93 +/- 6 pmol/l at 90 min and in the Type 2 diabetic patients from a similar basal level of 25 +/- 2 pmol/l to a higher peak of 133 +/- 7 pmol/l at 60 min. Glucose dependent insulinotropic polypeptide concentrations were significantly higher in Type 2 diabetic patients compared with the normal subjects at 30 min (p less than 0.001), 60 min (p less than 0.01) and from 210-240 min (p less than 0.05) during the meal tolerance test. The groups were subdivided on the basis of degree of obesity and glucose dependent insulinotropic polypeptide concentrations were still higher in the diabetic subgroups compared with the normal subjects matched for weight. Type 2 diabetes mellitus is associated with an exaggerated glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals which is independent of any effect of obesity.

The plasma glucose and insulin response to a standardized meal test breakfast was compared with the time-honored glucose tolerance test in the same normal healthy subjects. The amplitude of glycemic excursion and between-subject variation was less with the more physiologic standardized test meal than with that seen with the glucose tolerance test. The glucose tolerance test's prime function is to amplify any glucose intolerance, thus aiding diagnosis, whereas a standardized meal gives a more clinically relevant metabolic status. The administration of serial test meals during the same day in a smaller group of normal subjects indicated, as seen previously with repeated glucose tolerance tests, a diminishing carbohydrate tolerance during the day.

The frequency of the dawn phenomenon has been studied in non-insulin-dependent diabetic (NIDDM) patients while they continued with their conventional therapy. Plasma glucose (PG) and immunoreactive insulin (IRI) were estimated hourly from 0300 to 0900 h in 19 NIDDM patients; 9 patients were treated by diet alone (group 1), and 10 patients were treated by diet and oral hypoglycemic agents (group 2). The dawn rise of plasma glucose was demonstrated in 17 (89.5%) of the 19 patients with mean +/- SE plasma glucose at 0300 h of 7.0 +/- 0.5 mM and at 0800 h of 8.4 +/- 0.6 (P less than .01). IRI in all patients rose from 14.7 +/- 1.3 microU/ml at 0500 h to 18.1 +/- 1.8 microU/ml at 0700 h (P less than .05). The changes in IRI levels at any time from 0300 to 0800 h in groups 1 and 2 when considered separately were insignificant. Thus, the dawn phenomenon occurs commonly in NIDDM patients taking their conventional therapy.

A dawn rise of plasma glucose (PG) and/or insulin, the 'dawn phenomenon', has been commonly reported in treated diabetic patients and normal subjects. To evaluate the effect of treatment on this phenomenon in non-insulin-dependent diabetics (NIDDMs), PG, C peptide, immunoreactive insulin (IRI), growth hormone (GH), cortisol, epinephrine, and norepinephrine were measured hourly between 24.00 and 09.00 h in 17 newly diagnosed untreated NIDDMs (group 1). The study was repeated in 11 patients after a year of treatment (group 2). The PG levels did not change significantly at any time from 03.00 to 08.00 h in group 1 but increased continuously from 6.7 +/- 0.5 mmol/l at 04.00 h to 7.8 +/- 0.5 mmol/l at 08.00 h (P less than 0.01) in group 2. IRI and C peptide decreased significantly after 07.00 h in both groups. GH and catecholamine changes were similar in group 1 and group 2. Cortisol levels showed a nadir at 02.00 h and a peak after 07.00 h in both groups. Our results demonstrate no dawn rise of mean PG, IRI and C peptide in newly diagnosed untreated NIDDMs but a significant rise of PG in the early morning period in NIDDMs after a year of treatment with diet alone and diet plus sulphonylureas. Therefore other factors such as treatment and/or duration of the diabetes may play an important role in the pathogenesis of the dawn phenomenon.

Five normal volunteer subjects within 10% of their ideal body weight received four isocaloric meals per day during two separate study periods. Each study period consisted of two consecutive days one week apart. The plasma glucose and insulin response was determined half-hourly throughout the second day of each of the two study periods. Good reproducibility of the glucose and insulin response to the standardised meals on the two comparative profile days was observed. Only at three points during the day was the plasma glucose significantly different between the profile days while no differences existed for plasma insulin. In addition, a separate group of four healthy normal volunteer subjects within 10% of their ideal body weight received four 50 g oral glucose tolerance tests on each of four days, ie on two consecutive days one week apart. During the second day of each study period half-hourly plasma glucose and insulin concentrations were determined. The within subject reproducibility of the plasma glucose and insulin response to the serial glucose loads was excellent. At one time point only was the mean plasma glucose for the group significantly different between the two study days. No statistically significant difference however was observed for the plasma insulin response between the two days. As the day progressed during both test procedures a small decrease in carbohydrate tolerance was observed. The amplitude of glycaemic excursions in response to the oral glucose tolerance tests was greater than that observed in response to the meal tolerance tests.

Controversy exists over differences in hormonal counterregulatory (CR) responses to human and porcine insulins with conflicting reports regarding the adrenaline, glucagon, growth hormone, cortisol and prolactin responses to the two species of insulin. It has been suggested that these differences may represent different central nervous system sensitivities to the two types of insulin. The CR responses to an intravenous bolus of 0.1 U/kg of neutral soluble semi-synthetic (SSHI) and biosynthetic (BHI) human insulins, porcine insulin and diluting medium as control were compared in six fasted normal male subjects. The plasma glucose fell similarly with all three insulins reaching a mean nadir of 1.5 +/- 0.2 mmol/l at 25 min. Peak responses to porcine, SSHI and BHI, respectively were: adrenaline--523 +/- 101, 424 +/- 62, 379 +/- 76 pg/ml; glucagon--0.064 +/- 0.01, 0.063 +/- 0.01, 0.078 +/- 0.01 nmol/l; cortisol--507 +/- 42, 539 +/- 65, 507 +/- 42 nmol; growth hormone--76 +/- 10, 76 +/- 5, 64 +/- 15 mU/l; prolactin--507 +/- 72, 608 +/- 103, 523 +/- 118 mU/l. These differences in CR response were not statistically significant. The results do not support the suggestion of a different hormonal counterregulatory response or central nervous system sensitivity to human and porcine insulins when administered by intravenous bolus injections to normal subjects.

Monoclonal antibody-based two-site immunoradiometric assays are described for human insulin, proinsulin, 65-66 split and 32-33 split proinsulin. The detection limits of the assays lie in the range 0.8-2.5 pM. The assays for 65-66 and 32-33 split proinsulins do not distinguish between these substances and their respective C-terminal di-desamino derivatives. The assay of 65-66 split proinsulin does not cross-react with insulin, proinsulin or 32-33 split proinsulin. This material was undetectable (less than 1.0 pM) in plasma taken after an overnight fast in eight normal male subjects and the maximum individual concentration reached in plasma taken during an oral glucose tolerance test of these subjects was 3.8 pM. The proinsulin assay cross-reacted 66% with 65-66 split proinsulin but not with insulin or 32-33 split proinsulin. The 32-33 split proinsulin assay cross-reacted 84 and 60% with proinsulin and 65-66 split proinsulin respectively. The insulin assay cross-reacted 5.3, 62 and 5.0% with intact proinsulin, 65-66 split proinsulin and 32-33 split proinsulin respectively. The very low concentration of 65-66 split proinsulin meant that this derivative did not interfere significantly with the specificity of the assays of proinsulin and insulin. The concentration of 32-33 split proinsulin could be calculated by subtracting the cross-reactivity of the measured proinsulin. The mean concentrations of insulin, proinsulin and 32-33 split proinsulin in eight young male subjects in the fasting state were (pM +/- S.E.M.) 20 +/- 0.3, 2.3 +/- 0.3 and 2.1 +/- 0.7 and at the maximum reached during an oral glucose tolerance test, 150 +/- 26, 9.9 +/- 1.4 and 19.7 +/- 6.0 respectively.

The hormonal and glycaemic responses to serial test meals have been well documented in normal subjects and in patients with insulin dependent diabetes. There is less information in patients with non-insulin dependent diabetes. We studied 39 newly diagnosed previously untreated non-insulin dependent diabetics. Each patient received four identical test meals over a 24 hour period and their plasma glucose and insulin levels were determined at frequent intervals throughout the study period. The results show that all the non-insulin dependent patients at diagnosis had large post-prandial glucose excursions, and that the post-prandial rise in insulin was delayed. The study also demonstrates that glucose and insulin profiles are dependent on the degree of obesity of the patient. Patients with non-insulin dependent diabetes have a greater degree of glucose intolerance in the morning in contrast to normal subjects whose glucose tolerance is best in the morning.

A highly specific two-site immunoradiometric assay for insulin was used to measure the plasma insulin response to 75 g glucose administered orally to 49 patients with non-insulin-dependent diabetes (NIDDM). The plasma insulin concentration 30 min after glucose ingestion was lower in the diabetic patients than in matched controls for both non-obese (11-83 pmol/l vs 136-297 pmol/l, p less than 0.01) and obese subjects (23-119 pmol/l vs 137-378 pmol/l, p less than 0.01). By means of another two-site immunoradiometric assay, the basal intact proinsulin level was found to be higher in the NIDDM patients than in the controls for both non-obese (7.1 [SEM 1.2] pmol/l vs 2.4 [0.4] pmol/l, p less than 0.01) and obese subjects (14.4 [2.2] pmol/l vs 5.9 [1.9] pmol/l, p less than 0.01). The basal level of 32-33 split proinsulin was also raised in NIDDM. Previous failure to show clear separation between normal and NIDDM insulin responses was probably due to the high concentrations of proinsulin-like molecules in the plasma of NIDDM patients. These substances cross-react as insulin in most, if not all, insulin radioimmunoassays but have very little biological insulin-like activity. It is therefore now possible and necessary to designate most NIDDM patients as insulin deficient.

1. The absorption of 6U of soluble human insulin following subcutaneous injection into the anterior abdominal wall, thigh and into the thigh following admixture with aprotinin was assessed in normal subjects. The plasma immunoreactive insulin profiles were determined during a 6 h post injection period in subjects receiving concomitantly somatostatin to suppress endogenous insulin secretion. 2. Subcutaneous injection of human insulin into the anterior abdominal wall compared with the thigh led to significantly higher incremental insulin levels between 30 and 50 min (P less than 0.05) followed by lower values at 240-300 min (P less than 0.05). The absorption of soluble human insulin from a subcutaneous depot is faster from the anterior abdominal wall compared with the thigh associated with a faster clearance from plasma. 3. Injection into the thigh of insulin admixed with aprotinin resulted in higher plasma insulin levels at 10 min (P less than 0.001) and 20 min (P less than 0.05) compared with insulin given alone. Similarly, the insulin level was significantly higher with the admixture between 10 and 20 min (P less than 0.05) compared with insulin into the anterior abdominal wall. 4. Admixture of insulin with aprotinin therefore leads to an acceleration of the early phase of absorption from subcutaneous tissue due to a local hyperaemic effect.

Newly diagnosed, previously untreated patients with type 2 diabetes mellitus (n = 6) were studied on two separate days after overnight fasts. On each day they were given a 500-kcal mixed meal plus an infusion of either porcine glucose-dependent insulinotropic polypeptide (GIP) (0.75 pmol/kg/min) or control solution (CS) from 0 to 30 min in random order. Frequent measurements of plasma glucose, C-peptide, insulin and GIP concentrations were made. Fasting GIP levels were similar on both days. During the meal plus GIP infusion plasma GIP levels increased from a basal value of 7.6 +/- 1.5 pmol/1 to a peak of 88.6 +/- 5.4 pmol/1 at 30 min. Following the meal infusion of CS GIP increased from a fasting level of 10.3 +/- 1.2 pmol/1 to a significantly lower peak of 58.0 +/- 8.3 pmol/1 at 60 min. During the meal plus GIP infusion GIP levels were higher at 10-45 min and at 90 min (P less than 0.05-0.001). Fasting and postprandial glucose, C-peptide and insulin levels were, however, similar on both study day. A supplementary infusion of porcine GIP with a mixed meal did not significantly alter the beta cell response or glucose tolerance in this group of patients with type 2 diabetes mellitus.

The plasma glucose, C-peptide and insulin responses to subcutaneously administered highly purified porcine, 'semi-synthetic' and 'biosynthetic' human isophane (NPH) insulin and diluting medium as control in normal male subjects were evaluated. Porcine and semi-synthetic human NPH insulins were administered at two dose levels of 0.15 and 0.30 U/kg body weight and biosynthetic human NPH at 0.15 U/kg body weight only. At the low dose level the three insulin preparations resulted in a similar maximal hypoglycaemic effect within 3-5 h after administration. However, over the remainder of the 11 h post-injection period, the plasma glucose level was lower after semi-synthetic human insulin. In contrast, at the 0.30 U/kg dose level, there was no difference in the early or late hypoglycaemic response between porcine and semi-synthetic human NPH insulins of equivalent pharmaceutical formulation. The clinical relevance of these findings needs further evaluation. The data suggest that for the 'intermediate-acting' NPH insulin preparations, both the species of insulin, nature and quantity of the retarding protein and their subsequent interaction may determine their time-action characteristics.

The interaction between soluble (Actrapid HM) and Lente (Monotard HM) human insulin preparations was examined in normal subjects. Incremental plasma insulin levels were determined following the subcutaneous administration of 6 U of soluble insulin admixed with 0.14 ml soluble insulin diluting medium, or 0.14 ml Lente diluting medium and injected either immediately or 5 min after preparation. For comparison separate but simultaneous injections of soluble (6 U) and Lente insulin (14 U) were administered subcutaneously. All injection volumes were identical. The incremental insulin levels were significantly greater between 60 and 90 min (p less than 0.05-0.01) following the administration of soluble insulin admixed with its own medium compared to the soluble insulin/Lente medium admixtures injected immediately and 5 min after preparation. There was no difference, however, in the plasma insulin profiles between the two soluble insulin/Lente medium schedules. The separate simultaneous administration of soluble and Lente insulin resulted in significantly higher plasma insulin levels at 30 and 90 min (p less than 0.05) when compared to the admixture injected immediately after preparation and from 30-120 min (p less than 0.05-0.01) compared to the admixture injected after 5 min. The two soluble/Lente insulin admixtures achieved similar plasma insulin profiles. Therefore when soluble human insulin is admixed with Lente human insulin and administered by subcutaneous injection immediately after admixing there is a significant reduction in the plasma insulin levels during the first 90 min in contrast to when the two preparations are given simultaneously by separate injection. Delaying the injection of the admixture for 5 min results in significantly lower insulin levels up to 120 min. These differences are reflected in the hypoglycaemic responses observed.

Aims To develop an algorithm that delivers an individualized dose of rapid-acting insulin after morning resistance exercise to counter post-exercise hyperglycaemia in individuals with Type 1 diabetes. Methods Eight people with Type 1 diabetes, aged 34 ± 7 years with HbA1c concentrations 72 ± 12 mmol/mol (8.7 ± 1.1%), attended our laboratory on two separate mornings after fasting, having taken their usual basal insulin the previous evening. These people performed a resistance exercise session comprising six exercises for two sets of 10 repetitions at 60% of the maximum amount of force that was generated in one maximal contraction (60% 1RM). In a randomized and counterbalanced order, the participants were administered an individualized dose of rapid-acting insulin (2 ± 1 units, range 0-4 units) immediately after resistance exercise (insulin session) by means of an algorithm or were not administered this (no-insulin session). Venous blood glucose concentrations were measured for 125 min after resistance exercise. Data (mean ± sem values) were analysed using anova ( P ≤ 0.05). Results Participants had immediate post-resistance exercise hyperglycaemia (insulin session 13.0 ± 1.6 vs. no-insulin session 12.7 ± 1.5 mmol/l; P = 0.834). The decline in blood glucose concentration between peak and 125 min after exercise was greater in the insulin exercise session than in the no-insulin session (3.3 ± 1.0 vs. 1.3 ± 0.4 mmol/l: P = 0.015). There were no episodes of hypoglycaemia (blood glucose <3.9 mmol/l). Conclusions Administration of rapid-acting insulin according to an individualized algorithm reduced the hyperglycaemia associated with morning resistance exercise without causing hypoglycaemia in the 2 h post-exercise period in people with Type 1 diabetes. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the glycemic and glucoregulatory hormone responses to low- and moderate-intensity morning resistance exercise ( RE) sessions in type 1 diabetes ( T1DM). Following maximal strength assessments ( 1RM), eight T1DM ( HbA1C:72 ± 12 mmol/mol, age:34 ± 7 years, body mass index:25.7 ± 1.6 kg/m2) participants attended the research facility on two separate occasions, having fasted and taken their usual basal insulin but omitting rapid-acting insulin. Participants performed six exercises for two sets of 20 repetitions at 30% 1RM during one session [low-intensity RE session ( LOW)] and two sets of 10 repetitions at 60% 1RM during another session [moderate-intensity RE session ( MOD)], followed by 65-min recovery. Sessions were matched for total mass lifted (kg). Venous blood samples were taken before and after exercise. Data (mean ± SEM) were analyzed using analysis of variance ( P ≤ 0.05). There were no hypoglycemic occurrences throughout the study. Blood glucose rose similarly between sessions during exercise ( P = 0.382), remaining comparable between sessions throughout recovery ( P > 0.05). There was no effect of RE intensity on metabolic acidosis ( P > 0.05) or peak growth hormone responses ( P = 0.644), but a tendency for greater catecholamine responses under LOW (individualized peak concentrations: adrenaline MOD 0.55 ± 0.13 vs LOW 1.04 ± 0.37 nmol/ L, P = 0.155; noradrenaline MOD 4.59 ± 0.86 vs LOW 7.11 ± 1.82 nmol/ L, P = 0.082). The magnitude of post-exercise hyperglycemia does not differ between equal volume low and moderate intensity RE sessions performed in the morning. [ABSTRACT FROM AUTHOR]

To examine glycemic and glucoregulatory responses to resistance exercise (RE) sessions of different volume in type 1 diabetes (T1DM). Eight T1DM (seven males: one female; age: 38 ± 6 years, HbA1C: 8.7 ± 1.0%/71 ± 11 mmol/mol) attended the research facility fasted and on four separate occasions, having taken their usual basal insulin, but omitted morning rapid-acting insulin. Participants completed a 1SET (14 min), 2SET (28 min), 3SET (42 min) RE session (eight exercises x 10 repetitions) at 67 ± 3% one-repetition-maximum followed by 60-min recovery, or a resting trial (CON). Venous blood samples were taken before and after exercise. Data (mean ± SEM) were analyzed using repeated-measures analysis of variance (P ≤ 0.05). RE did not induce hypoglycemia (BG < 4 mmol/L). During recovery, blood glucose (BG) concentrations remained above pre-exercise after 1SET (15-60 min, P < 0.05) and 2SET (0-60 min, P < 0.05) but comparable (P > 0.05) with pre-exercise after 3SET. BGIAUC(area-under-curve) (mmol/L/60 min) was greater after 1SET and 2SET vs CON (1SET 103.6 ± 36.9 and 2SET 128.7 ± 26.1 vs CON -24.3 ± 15.2, P < 0.05), but similar between 3SET and CON (3SET 40.7 ± 59.3, P > 0.05). Under all trials, plasma creatine kinase levels at 24 h post-exercise were similar (P > 0.05) to pre-exercise. RE does not induce acute hypoglycemia or damage muscle. BG progressively rose after one and two sets of RE. However, inclusion of a third set attenuated exercise-induced hyperglycemia and returned BG to that of a non-exercise trial. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is associated with a continuous systemic inflammatory response. Furthermore, COPD is associated with an excess risk for cardiovascular disease and type II diabetes. Systemic inflammation in other populations is a factor in atherogenesis and has been associated with insulin resistance. We assessed the association between systemic inflammation and insulin resistance in non-hypoxaemic patients with COPD. Fasting plasma glucose, insulin and inflammatory mediators were measured in 56 patients and 29 healthy subjects. Body mass index (BMI) and height squared fat- and fat-free-mass index were similar between subject groups. Using homeostatic modelling techniques, mean (SD) insulin resistance was greater in the patients, 1.68 (2.58) and 1.13 (2.02) in healthy subjects, p = 0.032. Fasting plasma insulin was increased in patients while glucose was similar to that in healthy subjects. Patients had increased circulating inflammatory mediators. Insulin resistance was related to interleukin-6 (IL-6), r = 0.276, p = 0.039, and tumour necrosis factor α soluble receptor I, r = 0.351, p = 0.008. Both IL-6 and BMI were predictive variables of insulin resistance r2 = 0.288, p < 0.05. We demonstrated greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation. This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To examine the effects of glibenclamide and repaglinide on glucose stimulated insulin release, incretins, oxidative stress and cell adhesion molecules in patients with type 2 diabetes suboptimally treated with metformin. Methods: A randomized clinical trial was performed recruiting 27 subjects (HbA1c between 7.5 and 10.5%) free from cardiovascular and renal disease. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), total antioxidant status, F2-isoprostane, interleukin-6 and cell adhesion molecules were measured during an oral glucose load at baseline and after eight weeks of treatment. The areas under the curve were analysed at 45, 60 and 120min (AUC45, AUC60, AUC120). Results: Significant improvements in glucose were observed with repaglinide (HBA1c: −1.5%, fasting glucose: −2.8mmol/L, 2-h glucose: −3.7mmol/L, AUC120: −18.9%) and glibenclamide (−1.0%, −2.2mmol/L, −2.5mmol/L, −17.5%). Repaglinide was also associated with an increase in the AUC60 and AUC120 for insulin (+56%, +61%) and C-peptide (+41%, +36%). GLP-1, GIP, IL-6, ICAM-1 and E-selectin levels did not change in either group. No association was observed between GLP-1, GIP-1 and plasma markers of oxidative stress. Conclusion: Repaglinide is associated with improved postprandial glycaemic control via insulin and C-peptide release. We observed no direct effects of glibenclamide or repaglinide on plasma levels of GLP-1 or GIP. We observed no associations of GLP-1 and GIP with plasma markers of oxidative stress. [Copyright &y& Elsevier]