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Aim: People of Black African ancestry, who are known to be at disproportionately high risk of type 2 diabetes (T2D), typically exhibit lower hepatic insulin clearance compared with White Europeans. However, the mechanisms underlying this metabolic characteristic are poorly understood. We explored whether low insulin clearance in Black African (BA) men could be explained by insulin resistance, subclinical inflammation or adiponectin concentrations., Methods: BA and White European (WE) men, categorised as either normal glucose tolerant (NGT) or with T2D, were recruited to undergo the following: a mixed meal tolerance test with C-peptide modelling to determine endogenous insulin clearance; fasting serum adiponectin and cytokine profiles; a hyperinsulinaemic-euglycaemic clamp to measure whole-body insulin sensitivity; and magnetic resonance imaging to quantify visceral adipose tissue., Results: Forty BA (20 NGT and 20 T2D) and 41 WE (23 NGT and 18 T2D) men were studied. BA men had significantly lower insulin clearance (P = 0.011) and lower plasma adiponectin (P = 0.031) compared with WE men. In multiple regression analysis, ethnicity, insulin sensitivity and plasma adiponectin were independent predictors of insulin clearance, while age, visceral adiposity and tumour necrosis factor alpha (TNF-α) did not significantly contribute to the variation., Conclusion: These data suggest that adiponectin may play a direct role in the upregulation of insulin clearance beyond its insulin-sensitising properties., (© 2021. The Author(s).)

Aims/hypothesis: Type 2 diabetes is more prevalent in black African than white European populations although, paradoxically, black African individuals present with lower levels of visceral fat, which has a known association with insulin resistance. Insulin resistance occurs at a tissue-specific level; however, no study has simultaneously compared whole body, skeletal muscle, hepatic and adipose tissue insulin sensitivity between black and white men. We hypothesised that, in those with early type 2 diabetes, black (West) African men (BAM) have greater hepatic and adipose tissue insulin sensitivity, compared with white European men (WEM), because of their reduced visceral fat., Methods: Eighteen BAM and 15 WEM with type 2 diabetes underwent a two-stage hyperinsulinaemic-euglycaemic clamp with stable glucose and glycerol isotope tracers to assess tissue-specific insulin sensitivity and a magnetic resonance imaging scan to assess body composition., Results: We found no ethnic differences in whole body, skeletal muscle, hepatic or adipose tissue insulin sensitivity between BAM and WEM. This finding occurred in the presence of lower visceral fat in BAM (3.72 vs 5.68 kg [mean difference -1.96, 95% CI -3.30, 0.62]; p = 0.01). There was an association between skeletal muscle and adipose tissue insulin sensitivity in WEM that was not present in BAM (r = 0.78, p < 0.01 vs r = 0.25 p = 0.37)., Conclusions/interpretation: Our data suggest that in type 2 diabetes there are no ethnic differences in whole body, skeletal muscle, hepatic and adipose tissue insulin sensitivity between black and white men, despite differences in visceral adipose tissue, and that impaired lipolysis may not be contributing to skeletal muscle insulin resistance in men of black African ethnicity.

Aims/hypothesis: Successful postprandial glycaemia management requires understanding of absorption patterns after meals containing variable complex carbohydrates. We studied eight young participants with type 1 diabetes to investigate a large low-glycaemic-load (LG) meal and another eight participants to investigate a high-glycaemic-load (HG) meal matched for carbohydrates (121 g)., Methods: On Visit 1, participants consumed an evening meal. On follow-up Visit 2, a variable-target glucose clamp was performed to reproduce glucose and insulin levels from Visit 1. Adopting stable-label tracer dilution methodology, we measured endogenous glucose production on Visit 2 and subtracted it from total glucose appearance measured on Visit 1 to obtain meal-attributable glucose appearance., Results: After the LG meal, 25%, 50% and 75% of cumulative glucose appearance was at 88 ± 21, 175 ± 39 and 270 ± 54 min (mean ± SD), whereas glucose from the HG meal appeared significantly faster at 56 ± 12, 100 ± 25 and 153 ± 39 min (p < 0.001 to 0.003), and resulted in a 50% higher peak appearance (p < 0.001). Higher apparent bioavailability by 15% (p = 0.037) was observed after the LG meal. We documented a 20 min deceleration of dietary mixed carbohydrates compared with dietary glucose for the HG meal and a twofold deceleration for the LG meal., Conclusions/interpretation: Absorption patterns may be influenced by glycaemic load and/or meal composition, affecting optimum prandial insulin dosing in type 1 diabetes.

Aims/hypothesis: Although maternal hyperglycaemia is associated with increased risk of adverse pregnancy outcome, the mechanisms of postprandial hyperglycaemia during pregnancy are poorly understood. We aimed to describe glucose turnover in pregnant women with type 1 diabetes, according to stage of gestation (early vs late gestation)., Methods: The rates of systemic glucose appearance (R(a)) and glucose disposal (R(d)) were measured in ten pregnant women with type 1 diabetes during early (12-16 weeks) and late (28-32 weeks) gestation. Women ate standardised meals--a starch-rich 80 g carbohydrate dinner and a sugar-rich 60 g carbohydrate breakfast--and fasted between meals and overnight. Stable-label isotope tracers ([6,6-(2)H(2)]glucose and [U-(13)C]glucose) were used to determine R(a), R(d) and glucose bioavailability. Closed-loop insulin delivery maintained stable glycaemic conditions., Results: There were no changes in fasting R(a) (10 ± 2 vs 11 ± 2 μmol kg(-1) min(-1); p = 0.32) or fasting R(d) (11 ± 2 vs 11 ± 1 μmol kg(-1) min(-1); p = 0.77) in early vs late gestation. There was increased hepatic insulin resistance (381 ± 237 vs 540 ± 242 μmol kg(-1) min(-1) × pmol/l; p = 0.04) and decreased peripheral insulin sensitivity (0.09 ± 0.04 vs 0.05 ± 0.02 μmol kg(-1) min(-1) per pmol/l dinner, 0.11 ± 0.05 vs 0.07 ± 0.03 μmol kg(-1) min(-1) per pmol/l breakfast; p = 0.002) in late gestation. It also took longer for insulin levels to reach maximal concentrations (49 [37-55] vs 71 [52-108] min; p = 0.004) with significantly delayed glucose disposal (108 [87-125] vs 135 [110-158] min; p = 0.005) in late gestation., Conclusions/interpretation: Postprandial glucose control is impaired by significantly slower glucose disposal in late gestation. Early prandial insulin dosing may help to accelerate glucose disposal and potentially ameliorate postprandial hyperglycaemia in late pregnancy., Trial Registration: ISRCTN 62568875, Funding: Diabetes UK Project Grant BDA 07/003551. H.R. Murphy is funded by a National Institute for Health Research (NIHR) research fellowship (PDF/08/01/036). Supported also by the Juvenile Diabetes Research Foundation (JDRF), Abbott Diabetes Care (Freestyle Navigator CGM and sensors free of charge), Medical Research Council Centre for Obesity and Related Metabolic Diseases and NIHR Cambridge Biomedical Research Centre.

Aims/hypothesis: We compared the symptoms of hypoglycaemia induced by insulin detemir (NN304) (B29Lys(epsilon-tetradecanoyl),desB30 human insulin) and equally effective doses of neutral protamine Hagedorn (NPH) insulin in relation to possible differential effects on hepatic glucose production and peripheral glucose uptake., Methods: After overnight intravenous infusion of soluble human insulin 18 participants with type 1 diabetes received subcutaneous injections of NPH insulin or insulin detemir (0.5 U/kg body weight) on separate occasions in random order. During the ensuing gradual development of hypoglycaemia cognitive function and levels of counter-regulatory hormones were measured and rates of endogenous glucose production and peripheral glucose uptake continuously evaluated using a primed constant infusion of [6,6-(2)H(2)]glucose. The study was terminated when plasma glucose concentration had fallen to 2.4 mmol/l or had reached a minimum at a higher concentration., Results: During the development of hypoglycaemia no difference between the two insulin preparations was observed in symptoms or hormonal responses. Significant differences were seen in rates of glucose flux. At and below plasma glucose concentrations of 3.5 mmol/l suppression of endogenous glucose production was greater with insulin detemir than with NPH insulin, whereas stimulation of peripheral glucose uptake was greater with NPH insulin than with insulin detemir., Conclusions/interpretation: In participants with type 1 diabetes subcutaneously injected insulin detemir exhibits relative hepatoselectivity compared with NPH insulin, but symptoms of hypoglycaemia and hormonal counter-regulation are similar., Trial Registration: ClinicalTrials.gov NCT00760448.

Aims/hypothesis: It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables., Subjects and Methods: We randomised 17 sedentary overweight male subjects (age 50 +/- 2.6 years, BMI 27.6 +/- 0.5 kg/m(2)) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic-euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg(-1) min(-1)]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning., Results: After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group., Conclusions/interpretation: Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise.

Aims/hypothesis: We hypothesised that loss of peripheral fat in HIV patients would result in decreased plasma adipocytokines, in particular adiponectin, and that this decrease would be associated with changes in VLDL, IDL and LDL apolipoprotein B kinetics., Methods: Plasma adiponectin, leptin and other cytokines were measured in uninfected control subjects (n=12) and three HIV-positive groups comprising treatment-naïve patients (n=15) and patients on triple antiretroviral therapy containing protease inhibitors (PI, n=15) or non-nucleoside reverse transcriptase inhibitors (NNRTI, n=25). VLDL, IDL and LDL apolipoprotein B kinetics were measured with an infusion of [1-(13)C] leucine. Regional body fat was measured with a dual energy X-ray absorptiometry scan. Insulin resistance was calculated using homeostasis model assessment (HOMA)., Results: Adiponectin (median [interquartile range]) was reduced in the treatment-naive (5.4 microg/ml [4.7-8.5]), PI (5.0 microg/ml [3.3-6.4]) and NNRTI (5.0 microg/ml [3.1-6.7]) groups compared with controls (9.7 microg/ml [6.9-13.3]) (p<0.05). In all subjects adiponectin correlated positively with HDL-cholesterol levels, the VLDL, IDL and LDL apolipoprotein B fractional clearance rates, and with the limb fat:lean body mass ratio (all p<0.01). Adiponectin correlated negatively with plasma triglyceride levels and HOMA (p<0.001). In a linear regression model that included HOMA, adiponectin was an independent predictor of VLDL and HDL-cholesterol levels and the IDL fractional clearance rate. TNF was higher in treatment-naive and PI subjects, and soluble TNF receptor superfamily, members 1A and 1B (previously known as TNF receptors 1 and 2) was higher in PI patients than in control subjects (p<0.05)., Conclusions/interpretation: Adiponectin levels are significantly reduced in treated and untreated HIV patients and are predictive of VLDL and IDL apolipoprotein B fractional clearance rates. Adiponectin may have a direct effect on lipoprotein metabolism, which may be independent of insulin.

Aims/hypothesis: The association of insulin detemir with non-esterified fatty acid binding sites on albumin may limit its transfer from the circulation into the extravascular extracellular space in adipose tissue and muscle, due to the capillary endothelial cell barrier. In the liver, the open sinusoids may expose hepatocytes to insulin detemir, enabling it to have a greater effect in the liver than in peripheral tissues., Methods: We investigated the effects of equipotent doses of insulin detemir and NPH insulin on hepatic glucose rate of appearance (Ra), peripheral glucose rate of disposal (Rd) and glycerol Ra (a measure of lipolysis) using stable isotope techniques. We also investigated the effects of these insulins on NEFA concentrations in seven healthy volunteers during a 16-h euglycaemic clamp. A higher dose of insulin detemir was also studied., Results: There was no difference in the glucose infusion profile between insulin detemir and NPH. Insulin detemir had a greater effect on mean suppression of glucose Ra (mean difference 0.24 mg kg(-1) min(-1); CI 0.09-0.39; p<0.01), and minimum glucose Ra, with minimum low dose detemir -0.10+/-0.15 mg.kg(-1).min(-1) and minimum NPH 0.17+/-0.10 mg.kg(-1).min(-1) (p<0.02). However, it had a lesser effect on mean suppression of NEFA concentrations (mean difference -0.10 mmol/l; CI -0.03 to -0.17; ANOVA, p<0.02) than NPH. The effect of insulin detemir on glucose Rd and glycerol Ra was not different from NPH. Following high-dose detemir, total glucose infused and maximum glucose Rd were higher (p<0.02, p<0.03) and plasma NEFA concentrations lower (p<0.01) than with low-dose determir., Conclusions/interpretation: This study suggests that insulin detemir, when compared to NPH insulin, has a greater effect on the liver than on peripheral tissues and thus has the potential to restore the physiological insulin gradient.

Aims/hypothesis: Growth hormone hypersecretion in Type 1 diabetes could exacerbate insulin resistance and contribute to declining glycaemic control. Our aim was to determine the effects of specific growth hormone blockade on insulin sensitivity and lipolysis in young adults with Type 1 diabetes., Methods: We studied the effects of two doses of a specific growth hormone antagonist (B2036-PEG; Somavert, Pharmacia Corporation, Milton Keynes, UK) on insulin sensitivity in seven young adults (17-22 yrs, 3M) with Type 1 diabetes. Subjects received 5 and 10 mg B2036-PEG, in random order for 3 weeks, with a 3-week washout. At baseline and following each treatment block, an overnight (03:00 to 08:00 h) insulin infusion for euglycaemia (5 mmol/l), followed by two-step hyperinsulinaemic euglycaemic clamp, using [6,6 2H2] glucose and 2H5 glycerol to measure glucose and glycerol turnover was performed., Results: Compared to baseline, overnight insulin requirements decreased with both doses: (means+/-SEM) 0.34+/-0.02 mU/Kg/min vs 0.25+/-0.01 (5 mg) (p=0.04), and 0.24+/-0.01 (10 mg) (p=0.004). IGF-I (ng/ml) decreased following 10 mg [223.5+/-23.9 vs 154.6+/-28.1 (p=0.005], but not 5 mg. Mean overnight non esterified fatty acid concentrations (mmol/l) decreased with 10 mg [0.51+/-0.04 vs 0.38+/-0.04 (p=0.03)], as did beta-hydroxybutyrate (mmol/l); [0.31+/-0.04 vs 0.15+/-0.02 (p=0.004)]. Glycerol production rate, an index of lipolysis, was lower following 10 mg (p=0.04), but insulin sensitivity during the clamp did not change with either dose., Conclusion/interpretation: Treatment with both doses of B2036-PEG reduced overnight insulin requirements. The 10 mg dose suppressed lipolysis and reduced IGF-I. Failure to show enhanced insulin sensitivity during the clamp with the 10 mg dose could reflect opposing actions of growth hormone and IGF-I.

Aims/hypothesis: The role of glucose sensing cells in the human hepatic portal system in the initiation of the neuroendocrine responses to acute hypoglycaemia is not known. We investigated the effect of raising blood glucose concentrations in the hepatic-portal vein on neurohumoral responses during induction of systemic hypoglycaemia in nine healthy male volunteers., Methods: Each subject received an insulin infusion (3 mU.kg(-1).min(-1)) on two occasions, in random order. Variable rate glucose infusion was used to maintain plasma glucose at 5 mmol/l for 60 min, then 3.2 mmol/l for 60 min. At 20 min prior to hypoglycaemia, subjects drank 20 g of glucose in water or water sweetened with saccharin. In five of the volunteers, the oral glucose was labelled with U-13C6 glucose, which showed peak systemic glucose absorption between 90 and 110 min. Five volunteers also repeated the study with a euglycaemic clamp., Results: Oral glucose was associated with a reduction in the early adrenaline response to hypoglycaemia, the area under the curve from 90 to 110 min falling from 24.02+/-20.84 (means +/- SD) to 15.26+/-13.65 nmol/l per 20 min, p<0.05. Symptom scores (area under curve) decreased from 99.72+/-91.86 to 16.39+/-94.71, p=0.008 (total), 51.8+/-68.61 to 7.78+/-41.61, p=0.03 (autonomic) and 54.17+/-50.61 to 8.6+/-57.99 with oral glucose, p=0.001 (neuroglycopenic). Oral glucose did not influence symptoms during euglycaemia., Conclusion/interpretation: Our data are compatible with the hypothesis that centrally mediated symptomatic and neuroendocrine responses are attenuated by glucose detection in the hepatic portal vein in humans.

Gestational diabetes affects 2-3% of pregnant women and is associated with foetal complications including macrosomia and an increased likelihood of developing diabetes in later life. We have therefore studied seven women with gestational diabetes and five control women both during the third trimester of pregnancy and again 2-3 months post-partum, using the minimal model analysis of the frequently sampled labelled ([6,6-2H2]-glucose) intravenous glucose tolerance test. Glucose tolerance (glucose Kd) was significantly reduced in the women with gestational diabetes compared with the normal pregnant women both in pregnancy (1.16 +/- 0.11 vs 1.78 +/- 0.23%/min; p < 0.05) and post-partum (1.47 +/- 0.22 vs 2.59 +/- 0.43%/min; p < 0.05) and increased significantly in the control women after delivery (p < 0.05). Glucose effectiveness was not significantly different between the women with gestational diabetes and the control group either during or after pregnancy. Insulin sensitivity was significantly lower during pregnancy than after delivery in the women with gestational diabetes (p < 0.05). There was no significant difference in basal insulin secretion in the two groups during pregnancy or post-partum. However, during pregnancy the control subjects significantly increased (p < 0.001) their insulin secretion over a period of 20 min in response to an intravenous glucose tolerance test (96.2 +/- 42.7 pmol/kg) compared with post-partum values (58.3 +/- 25.2 pmol/kg) while in the women with gestational diabetes insulin secretion was similar in pregnancy (65.5 +/- 9.3 pmol/kg) and after delivery (57.7 +/- 15.7 pmol/kg). These data suggest that the glucose intolerance in gestational diabetes compared to normal pregnancy is due to reduced insulin sensitivity and an impaired ability in gestational diabetes to increase insulin secretion in response to glucose.

We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable isotope gas-chromatography mass-spectrometry method in six patients with non-insulin-dependent diabetes mellitus (NIDDM) (four males, two females, age 57.5 +/- 2.2 years (mean +/- SEM), weight 88.2 +/- 5.5 kg, glycated haemoglobin (HbA1) 8.5 +/- 0.5%, plasma total cholesterol concentration 5.7 +/- 0.5 mmol/l, triglyceride 3.8 +/- 0.9 mmol/l, high-density lipoprotein (HDL) cholesterol 1.0 +/- 0.1 mmol/l) and six non-diabetic subjects matched for age, sex and weight (four males, two females, age 55.7 +/- 2.8 years, weight 85.8 +/- 5.6 kg, HbA1 6.5 +/- 0.1%, plasma total cholesterol concentration 5.7 +/- 0.5 mmol/l, triglyceride 1.2 +/- 0.1 mmol/l, HDL cholesterol 1.4 +/- 0.1 mmol/l). HbA1, plasma triglyceride and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the diabetic patients than in the non-diabetic subjects (p = 0.006, p = 0.02 and p = 0.004, respectively). VLDL apoB absolute secretion rate was significantly higher in the diabetic patients compared with the non-diabetic subjects (2297 +/- 491 vs 921 +/- 115 mg/day, p < 0.05), but there was no significant difference in the fractional catabolic rate of VLDL apoB. There was a positive correlation between VLDL apoB secretion rate and (i) fasting C-peptide (r = 0.84, p = 0.04) and (ii) mevalonic acid concentration (r = 0.83, p < 0.05) in the diabetic patients but not in the non-diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the effect of gender on catecholamine responses to hypoglycaemia, single-step euglycaemic-hypoglycaemic clamps have been performed in 14 healthy men and 17 women. Adrenaline responses were 44% lower in females (p < 0.01) and noradrenaline 17% lower (p = 0.08). In response to low-dose intravenous insulin infusion (0.3 mU.kg-1.min-1), plasma glucose fall and counterregulation in seven men and seven women had a different course (p < 0.001), with different glucose kinetics. In men, endogenous glucose output recovered quickly to levels that exceeded basal; in women suppression of endogenous glucose output was more prolonged, without rates ever exceeding basal (p < 0.05). Peripheral glucose uptake was stimulated in men only. The hormones of acute glucose counterregulation (catecholamines and glucagon) did not differ between the sexes during this challenge, the catecholamine response in the women being supported by the continuous fall in plasma glucose. These results suggest that: 1) catecholamine responses to moderately controlled hypoglycaemia are diminished in women, and 2) peripheral insulin sensitivity in men is enhanced over that of women but hepatic sensitivity to insulin may be greater in women.

Leucine production rate, metabolic clearance rate and oxidation rate were measured in 10 Type 1 (insulin-dependent) diabetic patients after 24 h insulin withdrawal, conventional insulin therapy and an overnight insulin infusion to maintain normoglycaemia, and in 10 control subjects. In the insulin-withdrawn patients, leucine concentration (259 +/- 17 mumol/l), production rate (2.65 +/- 0.29 mumol . min-1 . kg-1) and oxidation rate (0.69 +/- 0.10 mumol . min-1 . kg-1) were significantly greater (p less than 0.001; p less than 0.05; p less than 0.005 respectively) than corresponding values in control subjects (127 +/- 6; 1.81 +/- 0.12; 0.19 +/- 0.02). Following conventional insulin therapy, leucine concentration (162 +/- 12 mumol/l) and oxidation rate (0.43 +/- 0.05 mumol . min-1 . kg-1) were lower than after insulin withdrawal but were still significantly greater than in control subjects (p less than 0.05; p less than 0.005). Although leucine concentration, production rate and metabolic clearance rate were normal after an overnight insulin infusion, leucine oxidation rate was still greater than normal (0.34 +/- 0.06 mumol . min-1 . kg-1; p less than 0.05). These results suggest that increased leucine concentration in insulin deficiency is due to elevated leucine production rate caused by increased proteolysis, and that leucine concentration is restored to normal by insulin treatment.