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Aims: People with recently-diagnosed type 1 diabetes mellitus (T1D) may undergo a transient period of glycaemic control with less exogenous insulin. Identification of predictors of this 'remission' could inform a better understanding of glycaemic control., Methods: Participants in the ADDRESS-2 study were included who had 1 or 2 assessments of remission status (coincident insulin dose and HbA1c measurement, with remission defined by ≤0.4 units insulin/kg-body-weight/day with HbA1c < 53 mmol/mol). Demographic and clinical presentation characteristics were compared according to remission status and predictors of remission were explored by logistic regression analysis., Results: 1470 first and 469 second assessments of remission status were recorded within 12 months of diagnosis of T1D. Step increases in the probability of remission were identified at age-at-diagnosis 20 years and 3 months after diagnosis (both p < 0.001). Among those aged < 20 years, remission was associated with male gender (p = 0.02), no ketoacidosis (p = 0.02) and fewer than 2 symptoms at presentation (p = 0.004). None of these characteristics predicted remission in those aged ≥ 20 years. In the subgroup with two assessments, transition to remission was independently associated with first remission assessment in months 1-2 post-diagnosis (p = 0.01), with age-at-diagnosis ≥ 20 years (p = 0.01) and, in those aged < 20 years, with an early HbA1c of <57 mmol/mol. Adiposity, ethnicity, autoantibody status and other autoimmune disease were unrelated to remission., Conclusions: For those diagnosed before 20 years of age, males, ketoacidosis-free, with fewer symptoms and low early HbA1c were more likely to experience remission, but remission was most likely in anyone aged ≥ 20 at diagnosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Insulin bolus calculators assist people with Type 1 diabetes (T1D) to calculate the amount of insulin required for meals to achieve optimal glucose levels but lack adaptability and personalization. We have proposed enhancing bolus calculators by the means of case-based reasoning (CBR), an established problem-solving methodology, by individualizing and optimizing insulin therapy for various meal situations. CBR learns from experiences of past similar meals, which are described in cases through a set of parameters (eg, time of meal, alcohol, exercise). This work discusses the selection, representation and effect of case parameters used for a CBR-based Advanced Bolus Calculator for Diabetes (ABC4D)., Methods: We analyzed the usage and effect of selected parameters during a pilot study (n = 10), where participants used ABC4D for 6 weeks. Retrospectively, we evaluated the effect of glucose rate of change before the meal on the glycemic excursion. Feedback from study participants about the choice of parameters was obtained through a nonvalidated questionnaire., Results: Exercise and alcohol were the most frequently used parameters, which was congruent with the feedback from study participants, who found these parameters most useful. Furthermore, cases including either exercise or alcohol as parameter showed a trend in reduction of insulin at the end of the study. A significant difference ( P < .01) was found in glycemic outcomes for meals where glucose rate of change was rising compared to stable rate of change., Conclusions: Results from the 6-week study indicate the potential benefit of including parameters exercise, alcohol and glucose-rate of change for insulin dosing decision support.

Aims/hypothesis: We have previously reported a high prevalence of non-alcoholic fatty liver disease (NAFLD) among women with previous gestational diabetes mellitus (pGDM). We wanted to confirm that intrahepatocellular lipid (IHCL) is associated with pGDM independently of adiposity and determine: (1) if VLDL metabolism is dysregulated; and (2) the extent to which NAFLD and IHCL account for the dysmetabolic phenotype in pGDM., Methods: We analysed data from a cohort of 234 women (114 with pGDM) and identified effects of pGDM on lipid and glucoregulation that were independent of ultrasound-diagnosed NAFLD. We then measured IHCL by MR spectroscopy in a representative subgroup (n = 36) and conducted detailed metabolic studies (IVGTT, VLDL apolipoprotein B [apoB] kinetics and palmitate turnover) and measurement of regional body fat by MRI to demonstrate effects of IHCL that were independent of a history of pGDM., Results: pGDM was associated with increased IHCL (p = 0.04) after adjustment for adiposity. Independently of IHCL, pGDM was associated with a lower IVGTT disposition index (p = 0.02) and acute insulin response to glucose (pGDM+/NAFLD-, 50% lower; pGDM+/NAFLD+, 36% lower; effect of pGDM, p = 0.03), increased VLDL apoB pool size (pGDM+/NAFLD-, 3.1-fold higher; pGDM+/NAFLD+, 1.2-fold higher; effect of pGDM, p = 0.02) and, at borderline significance (p = 0.05), increased rate of VLDL apoB synthesis., Conclusions/interpretation: pGDM is associated with increased IHCL independently of adiposity. The increased liver fat contributes to the phenotype, but pGDM status is independently associated with diminished insulin secretion and (shown for the first time) augmented VLDL metabolism. IHCL with pGDM may compound a dysmetabolic phenotype.

Context: Insulin is pivotal in regulating hepatic lipid synthesis, metabolism, and export., Objective: We tested the hypothesis that intrahepatic insulin exposure is an important determinant of intrahepatocellular lipid (IHCL), taking into account regional adiposity and both glucoregulatory and antilipolytic insulin sensitivity., Research Design and Methods: We compared 21 European males with known nonalcoholic fatty liver disease (NAFLD) with 19 healthy male controls. Insulin sensitivity, secretion, and percentage hepatic extraction were derived from iv glucose tolerance test (IVGTT) glucose, insulin, and C-peptide concentrations. Intrahepatic insulin exposure was calculated as percentage hepatic insulin extraction multiplied by basal or IVGTT insulin secretion. IHCL was quantified by proton magnetic resonance spectroscopy. Total and regional adipose tissue was measured using whole body magnetic resonance imaging., Results: Percentage hepatic extraction of newly secreted insulin differed between cases with NAFLD and controls at borderline significance (median, 76 vs. 83%; P = 0.07). Cases had higher intrahepatic insulin exposure than controls, both in the basal (34 vs. 18 pmol; P = 0.0002) and glucose-stimulated states (58 vs. 24 pmol; P = 0.01). IHCL was significantly related to both basal (r(s) = 0.62; P < 0.0001) and IVGTT intrahepatic insulin exposure (r(s) = 0.47; P = 0.002). As predictors of IHCL, both basal and IVGTT intrahepatic insulin exposure were dependent on the waist-to-hip ratio and homeostasis model assessment insulin resistance, but not on magnetic resonance imaging fat measures or IVGTT insulin sensitivity., Conclusions: Men with NAFLD have higher intrahepatic insulin exposure than controls. This correlates with IHCL, but the principal determinants of IHCL were fat distribution and hepatic rather than peripheral insulin resistance.

Introduction: Control algorithms for closed-loop insulin delivery in type 1 diabetes have been mainly based on control engineering or artificial intelligence techniques. These, however, are not based on the physiology of the pancreas but seek to implement engineering solutions to biology. Developments in mathematical models of the β-cell physiology of the pancreas have described the glucose-induced insulin release from pancreatic β cells at a molecular level. This has facilitated development of a new class of bio-inspired glucose control algorithms that replicate the functionality of the biological pancreas. However, technologies for sensing glucose levels and delivering insulin use the subcutaneous route, which is nonphysiological and introduces some challenges. In this article, a novel glucose controller is presented as part of a bio-inspired artificial pancreas., Methods: A mathematical model of β-cell physiology was used as the core of the proposed controller. In order to deal with delays and lack of accuracy introduced by the subcutaneous route, insulin feedback and a gain scheduling strategy were employed. A United States Food and Drug Administration-accepted type 1 diabetes mellitus virtual population was used to validate the presented controller., Results: Premeal and postmeal mean ± standard deviation blood glucose levels for the adult and adolescent populations were well within the target range set for the controller [(70, 180) mg/dl], with a percent time in range of 92.8 ± 7.3% for the adults and 83.5 ± 14% for the adolescents., Conclusions: This article shows for the first time very good glucose control in a virtual population with type 1 diabetes mellitus using a controller based on a subcellular β-cell model., (© 2012 Diabetes Technology Society.)

Aims/hypothesis: Our aim was to define the level of glycaemia at which pancreatic insulin secretion, particularly first-phase insulin release, begins to decline., Methods: Plasma glucose and insulin concentrations were measured during an IVGTT in 553 men with non-diabetic fasting plasma glucose concentrations. In 466 of the men C-peptide was also estimated. IVGTT insulin secretion in first and late phases was assessed by: (i) the circulating insulin response; (ii) population parameter deconvolution analysis of plasma C-peptide concentrations; and (iii) a combined model utilising both insulin and C-peptide concentrations. Measurements of insulin sensitivity and elimination were also derived by modelling analysis., Results: As fasting plasma glucose (FPG) increased, IVGTT first-phase insulin secretion declined by 73%, 71% and 68% for the three methods respectively. The FPG values at which this decline began, determined by change point regression, were 4.97, 5.16 and 5.42 mmol/l respectively. The sensitivity of late-phase insulin secretion to glucose declined at FPG concentrations above 6.0 mmol/l. Insulin elimination, but not insulin sensitivity, varied with FPG., Conclusions/interpretation: The range of FPG over which progressive loss of the first-phase response begins may be as low as 5.0 to 5.4 mmol/l, with late-phase insulin responses declining at FPG concentrations above 6.0 mmol/l.

Plasma homocysteine levels are lowered by insulin and can be elevated in insulin-resistant states. However, it is uncertain whether homocysteine and insulin resistance or components of the metabolic (insulin resistance) syndrome are related in healthy individuals. Total homocysteine concentrations were measured by gas chromatography-mass spectrometry in samples from 100 male participants in the second follow-up cohort of the Heart Disease and Diabetes Risk Indicators in a Screened Cohort Study. Members of this cohort have each undergone an iv glucose tolerance test with measurement of insulin sensitivity by minimal model analysis. Age ranged from 31--62 yr (mean, 46.8), body mass index from 20.6--36.5 kg/m(2) (mean, 26.3), insulin sensitivity from 0.0--9.6 min/mU.L (mean, 2.32), and homocysteine concentrations from 7.5--30.6 micromol/L (mean, 12.2). In univariate correlation, homocysteine concentrations were unrelated to insulin sensitivity or to components of the metabolic syndrome, including fasting serum triglycerides, high density lipoprotein cholesterol, high density lipoprotein subfraction 2 cholesterol, blood pressure, uric acid, systolic blood pressure, or body mass index. These measures were, nevertheless, highly intercorrelated. These findings strengthen the possibility that in healthy humans, homocysteine metabolism is not substantially affected by insulin action.

Objective: To study the effects of long-term growth hormone (GH) treatment on lipid metabolism and carbohydrate tolerance in GH-deficient adults., Design: Open trial of GH treatment for 4 years. GH dose was (median, range) 0.025 (0.010-0.050) IU/kg daily., Patients: Thirteen GH-deficient hypopituitary adults (seven men, six women), aged (median, range) 47 (24-65) years were followed for 4 years., Measurements: Fasting lipids, lipoproteins, apolipoproteins, glucose and insulin concentrations were measured at yearly intervals during GH therapy. A 75-g oral glucose tolerance test (OGTT) was also performed yearly, during which circulating glucose and insulin were measured at 30-minute intervals for 3 h., Results: Fasting total and low density lipoprotein (LDL) cholesterol concentrations decreased on GH therapy, but no change was observed in fasting triglyceride or high density lipoprotein (HDL) concentrations. Compared to pretreatment values, total and LDL cholesterol levels were significantly lower at 1 year (mean +/- SEM) (6.39 +/- 0.46 vs. 5.71 +/- 0.38 mmol/l, P < 0.05; 4.46 +/- 0.36 vs. 3.24 +/- 0.20 mmol/l, P < 0.01, respectively) and the reductions were maintained for the 4 years. Apolipoproteins A-1 and B did not differ significantly from the pretreatment levels. Fasting plasma glucose increased significantly at the first year (4.9 +/- 0.1 vs. 5.3 +/- 0.1 mmol/l, P < 0.05) but it returned to the pretreatment value in the following years. Fasting plasma insulin increased significantly at 1 year (4.3 (1.0-13.6) vs. 11.9 (1.2-26.9) mU/l, P < 0.05) and showed a progressive downward trend but remained significantly raised throughout the subsequent years. The 3-h area under the glucose curve (AUC) during the OGTT tended to be increased at the first year (P = 0.07) and it returned to the pretreatment level in the following years. The AUC of plasma insulin was significantly raised at 1 year (P = 0.024) and it returned to the pretreatment level in the following years., Conclusions: Four years of GH therapy in GH-deficient adults resulted in a sustained improvement in total and LDL cholesterol concentrations. Mild fasting hyperinsulinaemia persisted, although an initial deterioration in glucose tolerance, associated with post-glucose hyperinsulinaemia, was not sustained.

1. We studied beta-cell function in 40 hypopituitary adults and in 36 matched control subjects. Hypopituitary patients were studied again at 1, 3 and 6 months during a double-blind placebo-controlled trial of growth replacement lasting for 6 months. Biosynthetic human growth hormone was given subcutaneously in a daily dose of 0.02-0.05 i.u./kg at bed time. Fasting insulin, intact proinsulin and 32-33 split proinsulin were measured by two-site immunoradiometric assays. 2. Hypopituitary patients were aged 19-67 years and had a body mass index of 27.7 (18.0-41.1) kg/m2. They were receiving replacement thyroxine, adrenal steroids and sex hormones and they were growth hormone deficient. Control subjects were matched for age, sex and body mass index. Hypopituitary patients with normal glucose tolerance and with impaired glucose tolerance were compared separately with subgroups of control subjects matched for age and body mass index. 3. Twenty-six hypopituitary patients had normal glucose tolerance and 14 had impaired glucose tolerance. All control subjects had normal glucose tolerance by World Health Organization criteria. Patients with impaired glucose tolerance were significantly older than those with normal glucose tolerance (P < 0.03). Hypopituitary patients with normal glucose tolerance compared with normal control subjects had a significantly lower fasting plasma glucose concentration (P < 0.01), a lower fasting insulin concentration (P < 0.006), a lower insulin-glucose ratio (P < 0.02) and a lower percentage of insulin to total insulin-like molecules [hypopituitary patients, 90% (81-96%); control subjects, 93% (78-97%); P < 0.02]. Hypopituitary patients with impaired glucose tolerance had similar glucose and insulin concentrations and insulin-glucose ratios as matched control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Type 2 diabetes is characterized by resistance to insulin action of glucose metabolism and lipolysis. First-degree relatives of diabetic patients are at increased risk of developing diabetes themselves and early metabolic abnormalities in these relatives may represent primary defects in the pathogenesis of diabetes. Our previous work has demonstrated impaired suppression of lipolysis after an oral glucose load in glucose-tolerant relatives of Asian origin, but not in European relatives. To investigate whether a more subtle defect exists in the European population we studied 8 first-degree relatives of European patients and 9 matched control subjects. All had normal glucose tolerance. Glycerol and glucose turnovers were measured using a primed constant infusion of the stable isotopic tracers [1,1,1,2,3(2)H5] glycerol and [6,6(2)H] glucose, basally and in response to a very low dose insulin infusion (0.005 units kg-1 h-1). The relatives had higher basal insulin concentrations (median (range): 49 (30 to 113) vs 28 (18 to 66) pmol 1(-1), p < 0.05) compared to controls, but basal glycerol and glucose turnovers and plasma concentrations of glycerol, glucose, and non-esterifed fatty acids (NEFA) were similar. Following insulin, the suppression of glycerol appearance in the circulation measured isotopically was significantly less complete in the relatives compared with controls (mean change +/- SEM: + 0.06 +/- 0.21 vs - 0.51 +/- 0.16 mumol kg-1 min-1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Type 2 diabetes is associated with abnormal lipoprotein levels and altered plasma concentrations of insulin, intact and 32, 33 split proinsulin. To investigate whether these are early features of the disease, we studied 36 normoglycaemic first-degree relatives of patients with Type 2 diabetes (13 European, 15 of Asian (Indian-subcontinent), and 8 of Afro-Caribbean origin) and 36 control subjects with no family history of diabetes. Relatives and controls were matched for age (mean +/- S.E. 33 +/- 2 vs 34 +/- 2 years), body mass index (23.7 +/- 0.5 vs 23.7 +/- 0.6 kg m-2), sex (17 M, 19 F) and ethnic origin. After an overnight fast, blood was sampled for measurement of serum lipids, plasma glucose and insulin, intact and 32, 33 split proinsulin by specific immunoradiometric assays. Relatives and controls had similar fasting concentrations of glucose (5.0 +/- 0.1 vs 4.9 +/- 0.1 mmol l-1), total cholesterol (4.51 +/- 0.13 vs 4.54 +/- 0.17 mmol l-1), HDL-cholesterol (1.21 +/- 0.06 vs 1.10 +/- 0.05 mmol l-1), LDL-cholesterol (2.84 +/- 0.14 vs 2.96 +/- 0.14 mmol l-1) and triglyceride (median (range) 0.78 (0.44-2.45) vs 0.83 (0.41-4.03) mmol l-1). Fasting levels of insulin (50.4 (18.9-174.0) vs 51.6 (10.0-118.0) pmol l-1, intact proinsulin (2.8 (0.1-15.0) vs 2.1 (0.6-6.4) pmol l-1 and 32, 33 split proinsulin (2.0(0-23.7) vs 1.6 (0.3-6.0) pmol l-1) were not significantly different between relatives and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: The assessment of insulin sensitivity requires an accurate and reproducible technique. The short insulin tolerance test is a simple and rapid method for screening large numbers of subjects when the fasting glucose level is normal. Conventionally, an insulin dose of 0.1 units/kg is used, but this may result in symptomatic hypoglycaemia in healthy thin subjects who are insulin sensitive. In order to overcome this problem we have employed a lower dose of insulin and have studied the reproducibility of this modified technique comparing it with the euglycaemic hyperinsulinaemic clamp., Design: Subjects were studied on two separate occasions, once by a short insulin tolerance test and on a second occasion by either a euglycaemic hyperinsulinaemic clamp (insulin infusion of 40 mU/m2/min) or a repeat short insulin tolerance test., Patients: Eleven healthy subjects were studied twice with a short insulin tolerance test. A further 10 healthy subjects received a short insulin tolerance test on one day and a euglycaemic hyperinsulinaemic clamp study on another occasion., Measurements: Insulin sensitivity was measured in the short insulin tolerance test using the slope of arterialized blood glucose concentration from 3 to 15 minutes after an intravenous bolus of short-acting insulin, 0.05 units/kg body weight. In the clamp study, insulin sensitivity was derived from the average amount of glucose infused at steady state (M) and the mean plasma insulin level (I)., Results: In the short insulin tolerance test no subject developed symptomatic or biochemical hypoglycaemia, defined as a blood glucose < 2.2 mmol/l. The (mean +/- SEM) insulin sensitivities for the 11 subjects studied twice were 174 +/- 10 and 179 +/- 11 mumol/l/min with a coefficient of variation of 6.9 +/- 2.6%. There was a close correlation between insulin sensitivity derived from the short insulin tolerance test and that obtained from the euglycaemic clamp studies (so-called M/I ratio) in the same subjects (r = 0.81; P < 0.005)., Conclusion: The short insulin tolerance test employing 0.05 units/kg insulin is a safe, valid and reproducible method for the assessment of insulin sensitivity.

Insulin analogues have been produced with high affinity for the insulin receptor and with affinity lower than that of native insulin, but differences in activity when administered in vivo to man are unconvincing. We have used very low dose insulin (0.005 units kg-1 h-1) to investigate possible differences in effect of these insulin analogues on lipolysis in seven healthy subjects. Only minor effects on blood glucose concentration were observed and glucose turnover measured isotopically with 6,6 2H glucose and leucine turnover measured with 1-13C leucine did not change significantly. Fatty acid levels decreased with insulin (area under curve, median (range) -23 (-41-10) mmol l-1) and with the low affinity analogue (-28 (-42-19) mmol l-1 h,), but the high affinity analogue had no significant effect compared with controls (high affinity analogue -8 (-28-35) mmol l-1 h; control +15 (11-53) mmol l-1). Glycerol production measured isotopically decreased with insulin (-0.54 (-1.50-0.63) mumol kg-1 min-1) and with the low affinity analogue (-0.74 (-1.76-0.72) mumol kg-1 min-1), but the high affinity analogue at these doses had no significant effect on glycerol turnover (-0.19 (-0.74-1.13) mumol kg-1 min-1). Thus at these low infusion rates insulin itself and the low affinity analogue suppressed lipolysis, as assessed by glycerol turnover and by circulating fatty acid concentrations. The high affinity analogue was cleared rapidly from the circulation producing no measurable increase in immunoreactive insulin concentrations, and no effect was observed on lipolysis.

Insulin sensitivity and postprandial thermogenesis were investigated at various stages of pregnancy to assess if changes in insulin sensitivity contribute to energy conservation during pregnancy. Cross-sectional and longitudinal studies were undertaken. Sixteen control non-pregnant women were compared with 10 women in the second trimester (2nd) and thirteen women in the third trimester (3rd) of uncomplicated pregnancy. Six women were studied at all three time points. The slope of plasma glucose decline following a bolus of intravenous insulin was used as an index of insulin sensitivity. Resting energy expenditure was measured with continuous indirect calorimetry. Postprandial thermogenesis was measured as the change in energy expenditure for the 2 h after a mixed meal. Results are expressed as mean +/- SEM or median (interquartile range). Insulin sensitivity was lower as pregnancy progressed (non-pregnant control 181 (177-205) vs 2nd 111 (100-112) vs 3rd 96 (80-109) mumol l-1 min-1, p < 0.001). Fasting insulin levels were significantly higher in the third trimester but not in the second trimester (non-pregnant control 1.9 (1.5-6.0) vs 2nd 3.1 (2.8-5.2) vs 3rd 8.6 (4.8-9.7) mU l-1, p < 0.05). Meal stimulated insulin levels were higher in the second and third trimesters compared to non-pregnant women (insulin area over 2 h, postmeal, non-pregnant control 78 +/- 10 vs 2nd 92 +/- 14 vs 3rd 145 +/- 14 mU l-1 h-1, p < 0.005). Postprandial thermogenesis was lowest in the third trimester (non-pregnant control 103 +/- 5 vs 2nd 74 +/- 8 vs 3rd 48 +/- 8 kJ, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The plasma glucose and insulin responses to oral glucose were studied in 44 women who had previously had gestational diabetes, but had reverted to normal glucose tolerance. Twenty were White, 14 Black, and 10 Asian. A group of race-, age- and weight-matched controls was also studied. Fasting values of glucose and insulin did not differ significantly between the study group and controls. During the 2 h 75-g OGTT the White and Black previously gestational-diabetic women had similar plasma glucose values to their controls, while the Asian previously gestational-diabetic women had significantly higher glucose values at 30 min (9.2 +/- 0.6 (+/- SE) vs 7.1 +/- 0.3 mmol l-1, p less than 0.02) and at 60 min (8.6 +/- 0.8 vs 6.2 +/- 0.4 mmol l-1, p less than 0.02). Compared with their race-matched controls, the White previously gestational-diabetic women had significantly lower insulin values at 60 min (median 41 range 2-91) vs 56 (15-118) mU l-1, p less than 0.05), and the Black previously gestational-diabetic women had lower values at both 30 min (17 (4-116) vs 53 (22-197) mU l-1) and 60 min (36 (4-148) vs 99 (12-169) mU l-1, p less than 0.05). The insulin values were similar during the OGTT in the Asian previously gestational-diabetic women and their controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: The aim of this study was to compare intermediary metabolism in glucose tolerant women with previous gestational diabetes and control women without a history of gestational diabetes., Subjects: Fifteen women with previous gestational diabetes and 15 controls individually matched for race, age and body mass index were included. Only subjects with normal glucose tolerance were included in this study., Methods: Plasma glycerol, 3-OH butyrate, non-esterified fatty acids (NEFA), glucose and insulin were measured fasting and following a 75 g oral glucose load., Results: The women with previous gestational diabetes and their matched controls were of similar racial origin, age and body mass index. There was no difference between those with previous gestational diabetes and controls in fasting glycerol, 3-OH butyrate, NEFA, glucose or insulin concentrations. Following the oral glucose load, glycerol, 3-OH butyrate and NEFA concentrations fell in both groups. However, compared with controls at 120 minutes, those with previous gestational diabetes had significantly higher concentrations of glycerol (median 57, range 24-216 vs 27, range 8-89 mumols/l, P less than 0.005) and 3-OH butyrate (9, range 1-18 vs 5, range 2-11 mumols/l, P less than 0.01). NEFA concentrations were similar in the two groups. Despite similar glucose concentrations during the oral glucose tolerance test the insulin response during the first 60 minutes following oral glucose was significantly reduced in the subjects with previous gestational diabetes when compared with controls (insulin area, 0-60 minutes; 2172, range 788-4767 vs 2830, range 996-4784 pmol min/l, P less than 0.05)., Conclusions: Women with a previous history of gestational diabetes, despite having normal glucose tolerance, have defective insulin release with resultant abnormalities of intermediary metabolism.

1. The purpose of the present study was to examine the ability of insulin to inhibit its own secretion in type 2 diabetes independently of the prevailing plasma glucose concentration. 2. The responses of the plasma C-peptide concentration to sustained hyperinsulinaemia were assessed during a 200 min isoglycaemic clamp study in 14 patients with type 2 diabetes and seven age- and weight-matched control subjects. The arterialized venous plasma glucose concentration was clamped at approximately 0.3 mmol/l below each subject's own basal level and was not permitted to rise above the basal level. 3. In the fasting state, the plasma C-peptide concentration was slightly, but not significantly, higher in the diabetic patients than in the control subjects (667 versus 413 pmol/l, respectively, P = 0.07), but it remained significantly higher in the diabetic patients during the clamp studies in absolute terms (minimum plasma C-peptide concentration 400 pmol/l in diabetic patients versus 151 pmol/l in control subjects, P less than 0.05) and was suppressed to a lesser extent when expressed as a percentage change from basal (35.8% in diabetic patients versus 59.4% in control subjects, P less than 0.01). 4. In order to investigate whether a high plasma glucose concentration was maintaining the plasma C-peptide concentration in the diabetic patients, six of these patients underwent a second clamp study at euglycaemia (plasma glucose concentration 5.2 mmol/l). Under these conditions, the plasma C-peptide concentration was suppressed to the same extent as in the control subjects (from 623 to 195 pmol/l, a change of 62.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: Polycystic ovary syndrome (PCOS) is said to be associated with hyperinsulinaemia. Insulin stimulates androgen production by ovarian tissue in vitro and previous studies have identified a positive correlation of insulin with androstenedione. The aim of the present study was to discover whether insulin levels correlate with clinical presentation and with markers of androgen transport and metabolism in women with PCOS., Design: Within-group analysis of clinical and biochemical characteristics of a consecutive series of women with PCOS, focusing on correlations of plasma insulin with clinical presentation and androgens. Insulin levels were also compared with a control group of normal women., Patients: Forty-seven women who presented with hirsutism, cycle abnormalities or both, with ultrasound proven PCOS, were recruited. Mean age was 26.6 +/- 0.7 years (mean +/- SEM), BMI 27.3 +/- 1.2 kg/m2., Measurements: Plasma insulin levels were measured at 30-minute intervals for 3 hours following a 75 g glucose load. Blood was also taken for measurement of testosterone (T), androstenedione (A), free testosterone (fT), sex hormone binding globulin (SHBG) and insulin-like growth factor-I (IGF-I). Androsterone glucoronide (AG), a marker of peripheral androgen metabolism, was also measured., Results: Neither basal insulin nor the sum of insulin measurements during the glucose tolerance test (sumINS) in women with PCOS were significantly different from a control group with normal ovaries. Within the PCOS group, basal insulin was greater in women with irregular cycles or amenorrhoea than in those with regular ovulatory menses (8.0 +/- 1.1 vs 3.1 +/- 1.5 mU/l, P less than 0.01) despite similarly raised androgen levels. Both basal insulin and sumINS correlated with BMI in women with PCO (r = 0.37, P less than 0.05 and r = 0.64, P less than 0.01 respectively) but not in controls. There was no significant correlation between insulin or IGF-I levels and T, A or AG despite a positive correlation of AG (but no other androgen) with BMI. SHBG showed an inverse correlation and fT correlated positively with sumINS (r = -0.51, P less than 0.01; r = 0.39, P less than 0.05). Regression analysis of each of the androgens on the other variables demonstrated no significant relationship between insulin and androgens., Conclusions: These data suggest that, in vivo, the major effect of insulin on androgen secretion is mediated by changes in SHBG rather than by direct stimulation of ovarian androgen production. Higher insulin concentrations in anovulatory compared with ovulatory women with hyperandrogenaemia may indicate that insulin resistance in the ovary contributes to the mechanism of anovulation in PCOS.

1. A study on seven Caucasian glucose-tolerant women with previous gestational diabetes and seven matched control subjects is presented. The insulin response to oral glucose, insulin sensitivity and fasting glucose production rates were measured by using a 75 g oral glucose tolerance test, an insulin tolerance test and a non-radioactive tracer, [6,6-2H]glucose, respectively. 2. Fasting plasma glucose levels were similar between the women with previous gestational diabetes and the control subjects (4.8 +/- 0.3 versus 4.7 +/- 0.2 mmol/l), as were fasting plasma insulin levels (median 4 m-units/l, range 1-13 m-units/l versus median 4 m-units/l, range 1-24 m-units/l). After oral glucose the 60 min plasma glucose levels in the women with previous gestational diabetes were significantly higher (8.5 +/- 0.6 versus 6.7 +/- 0.8 mmol/l, P less than 0.05), whereas the plasma insulin level was significantly lower at both 30 min (median 23 m-units/l, range 4-47 m-units/l versus median 55 m-units/l, range 23-100 m-units/l, P less than 0.02) and at 60 min (median 23 m-units/l, range 4-43 m-units/l versus median 60 m-units/l, range 16-126 m-units/l, P less than 0.02). 3. Insulin sensitivity, expressed as the slope of the regression line of plasma glucose level against time after intravenous infusion of insulin (0.05 unit/kg), was similar in the women with previous gestational diabetes and the control subjects (mean slope, -0.17 +/- 0.01 versus -0.17 +/- 0.01). 4. Fasting glucose production rates were similar in the women with previous gestational diabetes and the control subjects (2.2 +/- 0.3 versus 1.9 +/- 0.1 mg min-1 kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Circulating hormone and metabolite profiles have been studied in ten patients with alcoholic cirrhosis, five patients with alcoholic hepatitis and/or fatty liver, and nine normal controls over a 12-h period of meals and activity. Blood glucose was elevated throughout the day in both cirrhotic and non-cirrhotic alcoholics (mean 12-h glucose; controls 5.38 +/- 0.16 (SEM) mmol/l; cirrhotics 6.98 +/- 0.30 mmol/l, P less than 0.001; non-cirrhotics 7.18 +/- 0.26 mmol/l, P less than 0.001). Non-cirrhotic alcoholics had an exaggerated insulin response to meals, whereas cirrhotic patients had hyperinsulinaemia throughout the day (mean 12-h insulin; controls 16.3 +/- 2.3 mU/l; cirrhotics 35.8 +/- 6.6 mU/l, P less than 0.02). Growth hormone levels were elevated only in patients with cirrhosis (mean 12-h growth hormone, 7.06 +/- 1.35 v. 0.85 +/- 0.17 micrograms/l, P less than 0.001). Serum cortisol was persistently elevated in cirrhotics but only in the evening in non-cirrhotic alcoholics. Lactate and pyruvate responses to meals were exaggerated in non-cirrhotic patients whereas in cirrhotics, levels were persistently raised. Blood glycerol was elevated in all alcoholic patients whereas ketone body levels were normal. Hypertriglyceridaemia was observed only in non-cirrhotic patients. No relationship between the endocrine and metabolic state was observed in either cirrhotic or non-cirrhotic patients.

The metabolic responses to 4-h infusions of adrenaline (3 micrograms kg-1 h-1) and cortisol (10 mg m-2 h-1 for 2 h followed by 5 mg m-2 h-1 for 2 h), separately and in combination, have been studied in six healthy subjects with concurrent somatostatin infusion (250 micrograms h-1). A combined infusion of adrenaline, cortisol, glucagon (180 ng kg-1 h-1) and somatostatin has also been studied. Somatostatin plus adrenaline and somatostatin plus cortisol resulted in hyperglycaemia (at 240 min, somatostatin plus adrenaline 11.4 +/- 0.4 mmol l-1, P less than 0.001; somatostatin plus cortisol 6.7 +/- 0.3 mmol l-1, P less than 0.05; somatostatin alone 4.9 +/- 0.4 mmol l-1). No synergistic effect on blood glucose was seen with adrenaline and cortisol together. When glucagon was added, blood glucose rose more rapidly than without glucagon (9.3 +/- 0.4 mmol l-1 v. 7.2 +/- 0.5 mmol l-1 at 45 min, P less than 0.001), but plateau values were similar. Plasma NEFA levels were raised by somatostatin plus adrenaline (0.55 +/- 0.04-1.82 +/- 0.11 mmol l-1 at 60 min). Somatostatin plus cortisol had no more effect on plasma NEFA than somatostatin alone. During the combined infusion of somatostatin plus adrenaline plus cortisol, a synergistic effect on plasma NEFA was observed (2.30 +/- 0.11 mmol l-1 at 60 min, P less than 0.01 v. somatostatin plus adrenaline). This occurred despite a small escape of insulin secretion. The lipolytic actions of adrenaline are potentiated by elevated circulating cortisol levels in insulin-deficient man.(ABSTRACT TRUNCATED AT 250 WORDS)

In view of the importance of insulin in hepatic cell proliferation and regeneration, disturbances might be expected in these processes in diabetics. The relative importnace of insulin replacement given intraportally rather than subcutaneously is discussed. Results are presented showing that even when normoglycaemia is achieved with peripheral insulin infusion using the 'artificial pancreas' there are still abnormalities in intermediary metabolism. The incidence of cirrhosis in diabetes is reviewed and it is concluded that the evidence is poor for an increase in diabetics. Finally it is shown that in the normal diabetic rat changes are observed after partial hepatectomy consistent with an increase in redox potential within the regenerating liver. Insulin treatment improves redox status but does not completely reverse the changes shown.

8 patients with severe progressive diabetic retinopathy despite continued mild carbohydrate intolerance on diet therapy alone were studied; each patient had presented initially with visual deterioration and none had experienced hyperglycaemic symptoms. By comparison with 8 carefully matched diet-treated diabetics without retinopathy, the retinopathy patients had increased circulating growth hormone levels and relative insulin deficiency. Several other factors of possible importance in the aetiology of microangiopathy, including circulating intermediary metabolites, platelet aggregation, blood viscosity, and lipids were similar in the two groups. It is possible that hypoinsulinaemia together with growth hormone excess may contribute to the development of eye disease in these patients with otherwise mild diabetes.

The effect of insulin deficiency on liver regeneration has been assessed in untreated v. insulin-treated streptozotocin (65 mg kg-1) diabetic rats, 12, 24 and 48 h after partial hepatectomy. Dry weight of regenerating liver increased from 12 to 48 h after partial hepatectomy and insulin treatment caused a further minor increase at 24 h. [6-3H]Thymidine uptake in untreated rats peaked at 24 h (12.5 +/- 3.4% of total cells labelled). Insulin therapy produced a delayed 168% rise in uptake at 48 h. Insulin deficiency alone in sham-operated animals caused a 33% decrease in hepatic [ATP], while [ADP] rose by 43% and [AMP] by 86% at 12 h. Partial hepatectomy produced only minor further abnormalities in untreated animals. Insulin therapy increased hepatic [ATP] and decreased [ADP] and [AMP] 12 h after partial hepatectomy, but [ATP] remained decreased (15%) and [ADP] and [AMP] increased (45% and 73% respectively) compared with insulin-treated sham-operated controls. Metabolite changes observed after partial hepatectomy in untreated animals, including a decrease in hepatic [glycogen] and increases in [triglyceride] and the ratios of [lactate]:[pyruvate] and [3-hydroxybutyrate]:[acetoacetate], were partially reversed by insulin treatment. Insulin deficiency thus impairs regeneration after partial hepatectomy and magnifies the decline in hepatic intracellular energy state and the metabolite changes associated with liver regrowth.

The metabolic sequelae of hyperprolactinaemia were studied over a 12 h period of normal meals and activity in nine young females hyperprolactinaemic subjects and fourteen matched controls. In the patients, fasting blood glucose and serum insulin concentrations were normal, as was the blood glucose response to meals; the insulin rise with meals was, however, exaggerated and hyperinsulinaemia persisted throughout the day (mean +/- SEM 12 h serum insulin, 26 +/- 8 vs. 16 +/- 9 mu/l, P < 0.01). Blood lactate, pyruvate and alanine response to meals was also increased. Blood glycerol (mean 12 h blood glycerol 0.06 +/- 0.01 vs. 0.09 +/- 0.01 mmol/l, P < 0.01) and blood 3-hydroxybutyrate (mean 12 h blood 3-hydroxybutyrate 0.03 +/- 0.01 vs. 0.05 +/- 0.01 mmol/l, P < 0.05) concentrations were lower in hyperprolactinaemic subjects. There was a strong negative correlation between mean insulin and mean 3-hydroxybutyrate levels in the afternoon period (rs = -0.92, P < 0.01). Excess circulating prolactin in young female is associated with normoglycaemic hyperinsulinaemia. The changes in blood metabolite levels observed are probably secondary to the increased insulin concentrations.

The metabolic effects of acute (4 h) and prolonged (24 h) growth hormone excess at pathophysiological concentrations were studied by growth hormone administration to normal subjects with and without somatostatin induced insulin deficiency. Acute growth hormone excess produced mild hyperinsulinaemia, but blood glucose concentrations were unaltered whereas chronic growth hormone excess caused a small (0.5 mmol/l) but significant rise in overnight-fasting blood glucose concentration together with a similar rise in fasting insulin levels (Mean +/- SEM 9 +/- 1 v 4 +/- 1 mU/l, p less than 0.01). When insulin secretion was suppressed by somatostatin, a hyperglycaemic effect of acute growth hormone excess was unmasked, and the hyperglycaemic effect of chronic growth hormone excess was exaggerated. Acute growth hormone administration without somatostatin had a mild ketogenic action despite stimulated insulin secretion but no change in plasma non-esterified fatty acid or blood glycerol levels was observed. Somatostatin magnified the ketogenic effect of acute growth hormone excess, and unmasked a lipolytic action. Prolonged growth hormone excess had a lipolytic action that was increased by somatostatin, although the ketogenic effect of growth hormone was only seen during somatostatin induced insulin deficiency. The acute hyperglycaemic, lipolytic and ketogenic actions of growth hormone in normal subjects are limited by a compensatory rise in insulin secretion although with chronic exposure hyperglycaemic and lipolytic effects are seen. In insulin-deficient states, however, elevated growth hormone levels could be important in promoting hyperglycaemia and hyperketonaemia.

1. A three-step hyperinsulinaemic euglycaemic clamp was performed in six uraemic patients before dialysis and after 3 months of treatment with continuous ambulatory peritoneal dialysis, and in seven matched normal control subjects. Glucose turnover was assessed basally and during the clamp using [3-3H]glucose as a tracer. 2. The glucose infusion rate required to maintain euglycaemia was insignificantly higher in normal subjects compared with undialysed uraemic subjects at each insulin infusion rate. 3. The isotopically assessed total glucose turnover was also similar in normal and uraemic subjects. Basal hepatic glucose output was again similar in uraemic and control subjects and output was suppressed to a similar degree at each insulin infusion rate. 4. After treatment with continuous ambulatory peritoneal dialysis, the glucose infusion rate and the total glucose turnover during the clamp rose significantly at all three insulin concentrations (P less than 0.05), but remained insignificantly different from normal control values. Hepatic glucose output was unchanged. 5. Peripheral insulin action was improved during continuous ambulatory peritoneal dialysis, but hepatic insulin action was unchanged.

Sensitivity to porcine insulin has been compared in overnight fasted hyperthyroid and control subjects using a euglycaemic clamp technique. Basal values for blood glucose, lactate, pyruvate, alanine, serum insulin and C-peptide were similar in the two groups, whilst blood glycerol (hyperthyroid 0.11 +/- 0.02 (mean +/- S.E.) vs. control 0.06 +/- 0.01 mmol/l, P less than 0.01) and blood 3-hydroxybutyrate (0.28 [0.03-0.79, range ]vs 0.09 [0.01-0.29 ]mmol/l, P less than 0.05) were increased in hyperthyroidism. During the 2 hour insulin infusion (0.05 U/kg/h), serum insulin plateaued at the same level (44 +/- 4 vs 44 +/- 1 mU/l) and insulin metabolic clearance rates were similar (1.21 +/- 0.10 vs 1.25 +/- 0.03 l/min). Serum C-peptide levels also decreased by similar amounts (40 +/- 8 vs 47 +/- 6%). The amount of glucose infused to maintain euglycaemia was identical during the second hour of insulin infusion (290 +/- 50 vs 330 +/- 30 mg/kg) as were the increments in lactate and pyruvate concentrations. Blood glycerol values decreased in both groups although values in hyperthyroid patients remained significantly higher than in controls. 3-Hydroxybutyrate concentrations fell to similar values in the two groups. These findings suggest that insulin-stimulated glucose metabolism and inhibition of ketogenesis are normal in hyperthyroidism.

The effect of insulin therapy on liver regeneration has been studied in normal fed rats 12, 24 and 48 h after partial hepatectomy. Dry weight of regenerating liver increased between 12 and 48 h after partial hepatectomy and was unaffected by insulin therapy. [6-3H] Thymidine uptake peaked at 24-h (24.7 +/- 2.4% of total liver cells) and insulin treatment had no additional effect. At 12-h after partial hepatectomy, hepatic [ATP] was decreased 15%, while [ADP] and [AMP] were increased 47% and 83% respectively compared with sham-operated animals. Partial hepatectomy also caused an increase in hepatic [triglyceride], a decrease in hepatic [glycogen] and an increase in the levels of glucose and several glycolytic intermediates. The hepatic redox ratios, [lactate]:[pyruvate] and [3-hydroxybutyrate]:[acetoacetate], were elevated. Insulin therapy had only minor effects on hepatic adenine nucleotide levels, intermediary metabolite concentrations or intrahepatic redox ratios after partial hepatectomy. These findings suggest a decreased hepatic intracellular energy state in regenerating liver; insulin therapy in normal rats does not influence this metabolic change nor the regenerative response.