S. V. Gelding

The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries

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.

Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries

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.

Validation of the low dose short insulin tolerance test for evaluation of insulin sensitivity.

OBJECTIVES 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.

Insulin resistance with respect to lipolysis in non-diabetic relatives of European patients with type 2 diabetes

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, 32H5] glycerol and [6, 62H] 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 μmol kg‐1 min‐1, p < 0.05). Plasma glycerol concentration decreased to a similar extent in relatives and controls, as did glucose and NEFA levels (mean change ± SEM: glycerol ‐12 ± 3 vs ‐8 ± 4 μmol 1‐1; glucose ‐0.37 ± 0.06 vs ‐0.30 ± 0.10 mmol.l‐1; NEFA ‐152 ± 48 vs ‐130 ± 32 μmol.1‐1). The change in glucose turnover was not different in relatives and controls (change ‐0.10 ± 0.03 vs ‐0.07 ± 0.06 mg kg‐1 min‐1). We conclude that glucose‐tolerant relatives of European origin exhibit subtle defects in insulin sensitivity with respect to lipolysis.

Insulin sensitivity in non-diabetic relatives of patients with non-insulin-dependent diabetes from two ethnic groups

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.

Increased secretion of 32,33 split proinsulin after intravenous glucose in glucose‐tolerant first‐degree relatives of patients with non‐insulin dependent diabetes of European, but not Asian, origin

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 β‐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.

Abnormalities of intermediary metabolism following a gestational diabetic pregnancy

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

Prohormone Convertase 1 in Obesity, Gestational Diabetes Mellitus, and NIDDM: No Evidence for a Major Susceptibility Role

Improved understanding of the primary molecular events underlying NIDDM and obesity is essential if more effective therapies are to be devised. Individual susceptibility to these interrelated conditions is under genetic influence (1), and clues to the identity of the major aetiological genes may come from physiological studies that pinpoint candidate pathways. A characteristic feature of NIDDM and certain prediabetic states, such as gestational diabetes mellitus (GDM), is a marked increase in the proportion of circulating insulin precursor molecules (proinsulin and split proinsulin intermediates) (2,3). Release of disproportionate amounts of these biologically inactive precursors may contribute to the relative insulin deficiency apparent in GDM and NIDDM (2). The processing of proinsulin to mature insulin is catalyzed by prohormone convertase (PC) enzymes active in (3-cell granules. PCI (also named PC3) cleaves intact proinsulin to produce 32,33 split proinsulin. PC2 and carboxypeptidase E (CPE) catalyze subsequent reactions (4). Functional defects in any of these candidate genes could contribute to the NIDDM phenotype. Furthermore, recent studies indicate a role for these loci in the determination of obesity. Mutations in the Cpe gene resulting in absent enzyme activity in islets and pituitary underlie the phenotype of the fat/fat mouse (5). More recently, Jackson et al. (6) reported on a family segregating two distinctPCi mutations. The mother was a compound heterozygote who had presented with childhood obesity, GDM, and a variety of

Genetic analysis of glucokinase and the chromosome 20 diabetes susceptibility locus in families with type 2 diabetes

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.

Differential metabolic actions of biosynthetic insulin analogues in normal man assessed by stable isotopic tracers

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 h) 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 h). Glycerol production measured isotopically decreased with insulin (‐0.54 (‐1.50–0.63) μmol kg−1 min−1) and with the low affinity analogue (‐0.74 (‐1.76–0.72) μmol 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) μmol 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.