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The rising prevalence of type 2 diabetes in the UK has necessitated a change in the delivery of diabetes care, with a shift of focus from hospital to community. The National Service Framework for Diabetes has enshrined this approach, and the new General Medical Services (GMS2) contract rewards primary healthcare professionals for developing high-quality diabetes care. New approaches cross the primary/secondary care divide and are patient focused. The evolution of diabetes care in the UK is illustrated by service developments in Newham, East London. [ABSTRACT FROM AUTHOR]

We describe the case of an African woman who was diagnosed with ketosis-prone diabetes with diabetes-associated autoantibodies, after being admitted for diabetic ketoacidosis (DKA) precipitated by her first presentation of systemic lupus erythematosus (SLE). She had a seven-year history of recurrent gestational diabetes (GDM) not requiring insulin therapy, with return to normoglycaemia after each pregnancy. This might have suggested that she had now developed type 2 diabetes (T2D). However, the diagnosis of SLE prompted testing for an autoimmune aetiology for the diabetes, and she was found to have a very high titre of GAD antibodies. Typical type 1 diabetes (T1D) was thought unlikely due to the long preceding history of GDM. Latent autoimmune diabetes of adults (LADA) was considered, but ruled out as she required insulin therapy from diagnosis. The challenge of identifying the type of diabetes when clinical features overlap the various diabetes categories is discussed. This is the first report of autoimmune ketosis-prone diabetes (KPD) presenting with new onset of SLE., Learning Points: DKA may be the first presentation of a multi-system condition and a precipitating cause should always be sought, particularly in women with a history of GDM or suspected T2D.All women with GDM should undergo repeat glucose tolerance testing postpartum to exclude frank diabetes, even when post-delivery capillary blood glucose (CBG) tests are normal. They should also be advised to continue CBG monitoring during acute illness in case of new onset diabetes.KPD comprises a spectrum of diabetes syndromes that present with DKA, but subsequently have a variable course depending on the presence or absence of beta cell failure and/or diabetes autoantibodies.KPD should be considered in a patient with presumed T2D presenting with DKA, especially if there is a personal or family history of autoimmune diabetes.LADA should be suspected in adults presumed to have T2D, who do not require insulin therapy for at least six months after diagnosis and have anti-GAD antibodies.Patients with autoimmune diabetes have an increased risk of other autoimmune diseases and screening for thyroid, parietal cell, coeliac and antinuclear antibodies should be considered.

Leptospirosis is an uncommon infectious disease that has protean clinical manifestations ranging from an innocuous 'flu-like' illness to potentially life-threatening multi-organ failure. Here we describe a case of Weil's disease that presented on the acute medical take with fever, jaundice and acute renal failure. We highlight the importance of careful history taking at the time of admission and how understanding the epidemiology and pathophysiology of leptospirosis enables a definitive diagnosis to be reached., (© 2015 Royal College of Physicians.)

The neurogenic differentiation-1 (NEUROD1), neurogenin-3 (NEUROG3), and hepatic nuclear factor-1alpha (TCF1) genes are interacting transcription factors implicated in controlling islet cell development and insulin secretion. Polymorphisms of these genes (Ala45Thr [NEUROD1], Ser199Phe [NEUROG3], and Ala98Val [TCF1]) have been postulated to influence the development of type 2 diabetes. We have investigated the role and interaction between these variants using PCR/restriction fragment-length polymorphism assays in 454 subjects recruited as part of a population survey in South India. Additionally, 97 South Indian parent-offspring trios were studied. Polymorphisms of all three genes were associated with either fasting blood glucose (FBG) and/or 2-h blood glucose (BG) in either the total dataset or when restricted to a normoglycemic population. A monotonically increasing effect, dependent on the total number of risk-associated alleles carried, was observed across the whole population (P < 0.0001 for FBG and 2-h BG), raising FBG by a mean of 2.9 mmol/l and 2-h BG by a mean of 4.3 mmol/l. Similarly, an ascending number of the same risk alleles per subject increased the likelihood of type 2 diabetes (P = 0.002). In conclusion, we observed a combined effect of variations in NEUROD1, NEUROG3, and TCF1 in contributing to overall glucose intolerance in a South Indian population.

Fibrocalculous pancreatic diabetes (FCPD) is a secondary cause of diabetes due to chronic pancreatitis. Since the N34S variant of the SPINK1 trypsin inhibitor gene has been found to partially account for genetic susceptibility to chronic pancreatitis, we used a family-based and case-control approach in two separate ethnic groups from the Indian subcontinent, to determine whether N34S was associated with susceptibility to FCPD. Clear excess transmission of SPINK1 N34S to the probands with FCPD in 69 Bangladeshi families was observed (P<.0001; 20 transmissions and 2 nontransmissions). In the total study group (Bangladeshi and southern Indian) the N34S variant was present in 33% of 180 subjects with FCPD, 4.4% of 861 nondiabetic subjects (odds ratio 10.8; P<.0001 compared with FCPD), 3.7% of 219 subjects with type 2 diabetes, and 10.6% of 354 subjects with early-onset diabetes (aged <30 years) (P=.02 compared with the ethnically matched control group). These results suggest that the N34S variant of SPINK1 is a susceptibility gene for FCPD in the Indian subcontinent, although, by itself, it is not sufficient to cause disease.

Haplotype combination 112/121 and its intrinsic variants (UCSNP43, -19, and -63) identified within the calpain 10 gene are associated with increased risk of type 2 diabetes in Mexican-Americans. We evaluated whether this haplotype combination and its constituent haplotypes and variants contribute to increased susceptibility to impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and type 2 diabetes in a South Indian population. Two study groups were used: 95 families ascertained through a proband with type 2 diabetes and 468 subjects recruited as part of an urban survey (69.1% with normal glucose tolerance, 12.8% with IFG/IGT, and 18.2% with type 2 diabetes). The four-locus haplotype combination 1112/1121 (UCSNP44, -43, -19, and -63) in South Indians conferred both a 10.7-fold increased risk for IFG/IGT (P = 0.001) and a 5.78- to 6.52-fold increased risk for type 2 diabetes in the two study groups (families P = 0.025, urban survey P = 0.015). A combination of the 1112 haplotype with the 1221 haplotype also appeared to increase risk for both IFG/IGT and type 2 diabetes. Contrary to what might be expected, quantitative trait analysis in the families found that transmission of the disease-related 1121 and 1112 haplotypes was associated with a reduced hip size and lower waist-to-hip ratio, respectively. This study supports the paradigm that specific haplotype combinations of calpain 10 variants increase risk of both IFG/IGT and type 2 diabetes. However, the relative infrequency of the "at-risk" combinations in the South Indian population suggests that calpain 10 is not a common determinant of susceptibility to type 2 diabetes.

Objective: To assess the role of beta cell failure in the development of autonomic dysfunction in patients with coronary artery disease., Design: Autonomic function was measured by standard clinical methods and by heart rate variability in 24 type II diabetic and 24 non-diabetic subjects with coronary artery disease. Quantitative estimates of pancreatic beta cell function (%beta) and insulin resistance were made from basal plasma glucose and insulin concentrations using a computer solved model. Fasting proinsulin levels provided an independent measure of beta cell function., Results: The circadian rhythm of sympathovagal balance (ratio of low to high frequency spectral components of heart rate variability) was significantly attenuated in patients with below median (%beta

Objective: Growth hormone (GH) replacement therapy in hypopituitary adults has been associated with a decreased urinary ratio of 11-hydroxy/11-oxo-cortisol metabolites (CoM). This could result from GH regulation of the activity of hepatic or renal 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1 and 2), the enzymes responsible for cortisol-cortisone interconversion, or alternatively it might reflect decreased cortisol availability. To elucidate this, we examined the effect of GH on urinary cortisol, cortisone and cortisol metabolites in hypopituitary adults at increasing doses of hydrocortisone replacement., Design: Patients received increasing twice daily doses of hydrocortisone (HC) (10/10, 20/10, 40/20 mg) each week, before and during 2 months of GH replacement (0.25 U/kg/week)., Patients: Seven hypopituitary adults (three men and four women, age range 47-64 years) with combined GH and ACTH deficiency. Three additional patients with GH deficiency, but intact ACTH reserve, were also studied., Measurements: Urine steroid metabolite profiles were measured in 24-hour urine collections by gas chromatography after each week of treatment. Urinary free cortisol and free cortisone were measured by radioimmunoassay as a measure of renal 11 beta-HSD-2 activity., Results: Total urinary CoM increased with rising doses of HC, but at each particular HC dose, were unchanged after GH (before versus after GH, median (range): 9.67 (7.86-12.59) versus 9.93 (8.31-14.08); 15.87 (12.37-31.39) versus 17.07 (12.64-23.81); 26.68 (19.07-42.14) versus 26.77 (8.01-37.62) mg/24 hours). The urine ratio 11-hydroxy/11-oxo-CoM decreased significantly with GH treatment, at each HC dose schedule (1.22 (1.02-1.96) versus 0.92 (0.83-1.63) P = 0.018; 1.53 (1.30-2.23) versus 1.23 (0.93-1.46) P = 0.018; 1.87 (1.45-2.70) versus 1.56 (1.22-1.79) P = 0.018). The urinary ratio tetrahydrocortisols/tetrahydrocortisone, an alternative index of 11 beta-HSD activity, also fell with GH therapy at each HC dose (P = 0.049; P = 0.018; P = 0.043). In contrast, the urinary 20-hydroxy/20-oxo-CoM ratio exhibited a small increase with GH, suggesting that the changes observed above were not simply due to changes in redox status. The patients with GH deficiency, but intact ACTH reserve, demonstrated changes in urine steroid profiles similar to the group receiving hydrocortisone replacement. Urinary free cortisone and urinary free cortisol/free cortisone ratios did not change with GH therapy, but the serum cortisol/ cortisone ratio fell significantly with GH therapy at each hydrocortisone dose., Conclusions: GH therapy decreases the urinary ratios 11-hydroxy/11-oxo-cortisol metabolites and tetrahydrocortisols/tetrahydrocortisone, but not urinary free cortisone or the urinary free cortisol/free cortisone ratio. This effect is not secondary to reduced cortisol availability. These findings provide further evidence for direct or indirect modulation of cortisol metabolism by growth hormone and suggest that this occurs at hepatic or an alternative site of 11 beta-hydroxysteroid dehydrogenase-1 activity.

Objective: Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history., Design: A cross-sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls., Patients and Methods: We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11)., Results: Results are expressed as mean +/- SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 +/- 0.7 vs LP 35.2 +/- 1.2, P < 0.01; OC 34.7 +/- 1.8 vs OP 37.8 +/- 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 +/- 9 vs LP 179 +/- 9, NS; OC 168 +/- 12 vs OP 133 +/- 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL2-cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38-0.62), LP 0.31 (0.26-0.44), P < 0.05; OC 0.34 (0.21-0.47), OP 0.21 (0.12-0.32) mmol/l, P < 0.01). Total HDL-cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL-cholesterol and with HDL2-cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL-cholesterol in women with polycystic ovaries., Conclusion: Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.

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)

Objective: The aetiology of non-insulin dependent diabetes is unknown, but defective insulin secretion is a feature. The disease also has a strong genetic basis and first-degree relatives of patients have an increased risk of future diabetes. To investigate whether beta-cell dysfunction is an early feature of the disease, we studied insulin secretion in healthy first-degree relatives of patients with non-insulin dependent diabetes., Design: Each subject underwent a 1-hour intravenous glucose tolerance test (0.3 g/kg)., Patients: Seventeen first-degree relatives of patients (10 of European and 7 of Asian (Indian subcontinent) origin) with normal glucose tolerance were compared with 17 matched control subjects with no family history of diabetes., Measurements: Plasma immunoreactive insulin (IRI) was measured by radioimmunoassay, and specific insulin, intact and 32,33 split proinsulin were measured by specific immunoradiometric assays (IRMA) for the 1st phase (0-10 minutes) and 2nd phase (10-60 minutes) responses. Glucose and intermediary metabolites were measured enzymatically., Results: Fasting concentrations of IRI, IRMA insulin, intact and 32,33 split proinsulin were similar in relatives and controls in each group. Fasting glucose levels were similar in European relatives and controls but lower in Asian relatives compared to their controls (mean +/- SE 4.9 +/- 0.2 vs 5.5 +/- 0.2 mmol/l, P < 0.05). Following intravenous glucose, European relatives had similar IRI and glucose levels to their controls. Secretion of 32,33 split proinsulin was increased in European relatives compared to their controls, significantly so for 2nd phase secretion (1st phase median (range): 71 (7-352) vs 55 (17-118) pmol/l min, NS; 2nd phase: 433 (115-1459) vs 234 (55-745) pmol/l min, P < 0.05). Secretion of IRMA insulin and intact proinsulin were similar in European relatives and controls (IRMA insulin: 1st phase 2757 (700-10,969) vs 2830 (632-4682) pmol/l min; 2nd phase 6387 (3006-15,865) vs 5284 (2060-18,605) pmol/l min; intact proinsulin: 1st phase 31 (13-113) vs 32 (16-72) pmol/l min; 2nd phase: 174 (87-737) vs 159 (97-298) pmol/l min). European relatives had a greater percentage of proinsulin-like molecules (intact + 32,33 split proinsulin) to total insulin (sum of IRMA insulin + intact + 32,33 split proinsulin) during the 2nd phase of secretion (9.1 (5.0-11.8) vs 5.9 (4.3-12.6)%, P < 0.05). In contrast, Asian relatives had similar secretion of IRI, IRMA insulin, intact and 32,33 split proinsulin to their controls. Glucose disappearance (KG) was similar in relatives and controls within each ethnic group (Europeans: relatives 725 +/- 101 vs controls 668 +/- 47/min; Asian: relatives 610 +/- 97 vs controls 783 +/- 936/min). Asian relatives had higher fasting circulating glycerol (65 +/- 7 vs 44 +/- 4 mumol/l, P < 0.05), non-esterified fatty acid (569 +/- 59 vs 375 +/- 64 mumol/l, P < 0.05) and 3-hydroxybutyrate levels (147 (44-187) vs 35 (21-57) mumol/l, P < 0.01) than their controls and this persisted following intravenous glucose. This difference was not observed in the European group., Conclusion: First-degree relatives of European patients with NIDDM possess early signs of beta-cell dysfunction, with increased and disproportionate secretion of 32,33 split proinsulin after intravenous glucose, whilst glucose tolerance is still normal.

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)

Mutations of the glucokinase gene (chromosome 7p) have been shown to cause some cases of familial maturity onset diabetes of youth (MODY) but few, if any, cases of late onset familial Type 2 diabetes. A further single large pedigree with MODY has shown linkage to a marker for the adenosine deaminase gene (ADA, chromosome 20q), although the diabetes susceptibility gene at this locus has not been identified. We have studied members of 19 families with familial Type 2 diabetes (including 10 European families, 6 families from the Indian subcontinent, and 3 families of Afro-Caribbean origin), 2 of which were of MODY type (and both European), with a glucokinase marker and a marker linked to ADA, to examine whether glucokinase, or the unknown defect on chromosome 20, are implicated in diabetes in our pedigrees. Several models were constructed for standard two-point linkage analysis. Glucokinase is not the cause of diabetes in all of these families but was excluded in only one MODY family. It was possible to exclude both loci in the second MODY pedigree. No evidence was found of linkage to either marker in this multi-ethnic population under the models used. At least one further locus is involved in determining susceptibility to MODY.

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.

Objective: Non-insulin-dependent diabetes is a heterogeneous disorder, the basis of which may differ in different ethnic groups. In order to investigate early metabolic abnormalities occurring during the development of the condition we assessed insulin secretion and insulin action in subjects predisposed to the later development of non-insulin-dependent diabetes from two different ethnic groups., Design: Subjects were studied on two separate occasions by an oral glucose tolerance test and a short insulin tolerance test., Patients: Twenty-four glucose-tolerant first-degree relatives of patients with non-insulin-dependent diabetes (12 of European and 12 of Asian origin) were compared with 24 ethnically matched control subjects with no family history of diabetes., Measurements: Insulin, proinsulin, glucose and intermediary metabolites were measured during a 75-g oral glucose tolerance test. Insulin sensitivity was assessed using a 15-minute insulin tolerance test (0.05 units/kg)., Results: Asian relatives compared to Asian controls had significantly higher fasting levels of immunoreactive insulin (83 +/- 17 vs 40 +/- 6 pmol/l, P < 0.05), which were not due to increased proinsulin. Blood glycerol concentrations were elevated (83 +/- 9 vs 51 +/- 4 mumol/l, P < 0.005), but fasting glucose and non-esterified fatty acid (NEFA) concentrations were similar. Relatives of European origin did not differ from their European controls in any of these measurements. The glucose response to oral glucose was similar in relatives and controls, irrespective of ethnic group. The insulin responses were non-significantly greater in relatives from both ethnic groups. Proinsulin levels were not significantly different. Asian relatives had higher circulating glycerol and NEFA levels after oral glucose than Asian controls, but these differences were not observed in the European group. Insulin sensitivity was reduced in the Asian relatives compared to their controls (183 +/- 7 vs 139 +/- 12 mumol/l/min, P < 0.01) but there was no difference in insulin sensitivity between the European relatives and European controls (167 +/- 11 vs 160 +/- 11 mumol/l/min)., Conclusions: First-degree relatives of non-insulin-dependent diabetic patients of Asian, but not of European, origin are insulin insensitive in terms of both glucose metabolism and lipolysis, and have true hyperinsulinaemia. This suggests that insulin insensitivity may be an early abnormality in the development of non-insulin-dependent diabetes in the Asian population.

Objective: Insulin insensitivity is a recognized feature of polycystic ovary syndrome (PCOS) but previous studies have suggested that circulating insulin concentrations are normal in hyperandrogenaemic women with regular cycles. The aim of this study was to examine the relationship between insulin sensitivity and menstrual pattern in women with PCO., Design: A cross-sectional study of insulin sensitivity in a cohort of PCO subjects with oligomenorrhoea compared to women with PCO and regular menstrual cycles and a group of normal control subjects., Subjects: Seventy-two women with polycystic ovaries on ultrasonography were studied. PCO subjects had clinical and/or biochemical evidence of hyperandrogenism; 53 had oligo/amenorrhoea (olig) and 19 had regular menses (reg). Results were compared with 31 control subjects. The groups were matched for age, weight and ethnic origin., Methods: Glucose and insulin responses to 75 g oral glucose were measured. Insulin sensitivity was assessed by the decline in plasma glucose following intravenous insulin (0.05 U/kg)., Results: Glucose area (mean +/- SEM) after oral glucose was increased slightly in both PCO groups compared with controls (olig 37.6 +/- 1.4, reg 36.0 +/- 1.8, control 33.7 +/- 0.9 mmol/l h, both P < 0.01). Insulin area median (interquartile range) in response to glucose was significantly greater in the oligomenorrhoeic group (346 (239-734) mU/l h), compared with both PCO with regular cycles (246 (148-355), P < 0.01) and controls (221 (147-277), P < 0.01). Insulin sensitivity was reduced (P < 0.01) in the oligomenorrhoeic group (147 +/- 9.2 mumol/l min) compared to controls (185 +/- 7.4) but was normal in PCO with regular cycles (182 +/- 12.5). Insulin sensitivity did not correlate significantly with plasma testosterone or with SHBG levels, but plasma insulin concentrations correlated negatively with SHBG levels (fasting insulin vs SHBG, r = -0.47, P < 0.01; insulin area vs SHBG, r = -0.41, P < 0.01)., Conclusions: Insulin insensitivity in polycystic ovary syndrome occurs when there is oligo/amenorrhoea but not when the menstrual cycle is regular. This is consistent with PCO and insulin insensitivity being separate abnormalities which when combined are associated with anovulation.

This study has investigated protein metabolism in adults with hypopituitarism before and after growth hormone (GH) replacement and in matched controls. Whole-body leucine turnover was measured in 16 GH-deficient adult hypopituitary patients (nine females and seven males) on standard thyroid, adrenal and sex hormone replacement and in 20 normal controls using primed continuous infusion of L-[1-13C]leucine. In seven of the patients, leucine turnover was restudied following 6 months' treatment with biosynthetic human GH (0.025-0.05 IU/kg body wt daily, with the final dose determined by patient tolerance). Compared with normal controls, hypopituitary patients had significantly reduced leucine flux (mean +/- SD: 97.8 +/- 24.9 vs 131.0 +/- 23.0 mumol.h-1 x kg-1; p < 0.001), reduced leucine incorporation into protein (80.4 +/- 20.9 vs 108.8 +/- 19.6 mumol.h-1 x kg-1; p < 0.001) and reduced leucine oxidation (17.4 +/- 4.8 vs 22.2 +/- 8.1 mumol.h-1 x kg-1; p < 0.05). Leucine turnover was similar in male and female patients. In the patients, leucine flux correlated positively with body weight (rho = 0.51, p < 0.05) and leucine incorporation in protein correlated positively with lean body mass (rho = 0.55, p < 0.05) and in male patients leucine flux correlated positively with serum insulin-like growth factor I (IGF-I) levels (rho = 0.71, p < 0.05). No significant relationship was observed with age or duration of hypopituitarism. Growth hormone replacement therapy did not produce a uniform effect on leucine metabolism. Mean values of leucine flux, oxidation and incorporation into protein increased, although the differences were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.