Beryl Barrow

Normalization of Insulin Responses to Glucose by Overnight Infusion of Glucagon-Like Peptide 1 (7–36) Amide in Patients With NIDDM

Glucagon-like peptide 1 (GLP-1) is a natural enteric incretin hormone, which is a potent insulin secretogogue in vitro and in vivo in humans. Its effects on overnight glucose concentrations and the specific phases of insulin response to glucose and nonglucose secretogogues in subjects with NIDDM are not known. We compared the effects of overnight intravenous infusion of GLP-1 (7-36) amide with saline infusion, on overnight plasma concentrations of glucose, insulin, and glucagon in eight subjects with NIDDM. The effects on basal (fasting) β-cell function and insulin sensitivity were assessed using homeostasis model assessment (HOMA) and compared with seven age- and weight-matched nondiabetic control subjects. The GLP-1 infusion was continued, and the first- and second-phase insulin responses to a 2-h 13 mmol/l hyperglycemic clamp and the insulin response to a subsequent bolus of the nonglucose secretogogue, arginine, were measured. These were compared with similar measurements recorded after the overnight saline infusion and in the control subjects who were not receiving GLP-1. The effects on stimulated β-cell function of lowering plasma glucose per se were assessed by a separate overnight infusion of soluble insulin, the rate of which was adjusted to mimic the blood glucose profile achieved with GLP-1. Infusion of GLP-1 resulted in significant lowering of overnight plasma glucose concentrations compared with saline, with mean postabsorptive glucose concentrations (2400–0800) of 5.6 ± 0.8 and 7.8 ± 1.4 mmol/l, respectively (P < 0.0002). Basal β-cell function assessed by HOMA was improved from geometric mean (1 SD range), 45% β (24–85) to 91% β (55–151) by GLP-1 (P < 0.0004). First-phase incremental insulin response to glucose was improved by GLP-1 from 8 pmol/l (-–33) to 116 pmol/l (12–438) (P < 0.005), second-phase insulin response to glucose from 136 pmol/l (53–352) to 1,156 pmol/l (357–3,748) (P < 0.0002), and incremental insulin response to arginine from 443 pmol/l (172–1,144) to 811 pmol/l (272–2,417) (P < 0.002). All responses on GLP-1 were not significantly different from nondiabetic control subjects. Reduction of overnight glucose by exogenous insulin did not improve any of the phases of stimulated β-cell function. Prolonged intravenous infusion of GLP-1 thus significantly lowered overnight glucose concentrations in subjects with NIDDM and improved both basal and stimulated β-cell function to nondiabetic levels. It may prove to be a useful agent in the reduction of hyperglycemia in NIDDM.

High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population

Summary A high proportion of the female patients who are members of maturity onset diabetes of the young (MODY) pedigrees, and whose diabetes mellitus is due to a glucokinase mutation, originally presented with gestational diabetes. To establish whether glucokinase mutations could be a common cause of gestational diabetes, we studied 50 subjects who presented with gestational diabetes and on follow-up had hyperglycaemia (5.5–10.0 mmol/l). Screening for glucokinase mutations using single-stranded conformational polymorphism (SSCP) analysis detected a missense mutation at position 299 (Gly299→ Arg) in three subjects. As two pedigrees in the Oxford area had the same glucokinase mutation, we suspected the role of a founder-effect, and carried out pedigree extension, haplotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area. One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects with the mutation were found to have the Z + 4/2 (GCK1/GCK2) haplotype, suggesting that the observed high prevalence of the Gly299→ Arg glucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs. [Diabetologia (1996) 39: 1325–1328]

Prevalence of diabetes mellitus and impaired glucose tolerance in parents of women with gestational diabetes

SummaryNuclear families of non-insulin-dependent diabetic (NIDDM) patients are uncommon, as usually one or both parents have died. In order to aid identification of complete nuclear families, we have ascertained the disease process at a younger age by studying subjects with previous gestational diabetes. One hundred women who had had gestational diabetes, age (±SD) 38 (6) years, were screened by fasting plasma glucose (fpg). Sixty-one were found to have either fasting hyperglycaemia (5.5≤fpg<7.8 mmol/l) or diabetes. Of these women 35 had both parents alive and the parents of 14 of these women agreed to the assessment of their metabolism by a continuous infusion of glucose with model assessment (CIGMA). Seven probands had impaired glucose tolerance (IGT) and seven were diabetic. They were age 35 (4) years and had body mass index (BMI) 26 (5) kg/m2. The parents were aged 62 (6) years and had BMI 29 (6) kg/m2 and their affection status was defined as presence of glucose intolerance (fpg or post-infusion achieved plasma glucose level >2 SD of an age and obesity matched population). In the 14 families, five probands (36%) had neither parent affected, six (43%) had one parent affected and three (21%) had both parents affected. Only three probands had a parent with diabetes as defined by World Health Organisation criteria. We concludes that the study of women who have had gestational diabetes allows detection of probands with diabetes or impaired glucose tolerance, who have both parents available for study. A substantial proportion had neither parent affected with impaired glucose tolerance or diabetes, similar to the nuclear families of NIDDM patients. The results are in accord with studies of nuclear families of NIDDM patients in suggesting polygenic inheritance or environmental influences rather than autosomal dominant inheritance with high penetrance.

Changes in amylin and amylin-like peptide concentrations and beta-cell function in response to sulfonylurea or insulin therapy in NIDDM.

OBJECTIVE Amylin, a secretory peptide of fi-cells, is the constituent peptide of islet amyloid, which is characteristic of NIDDM, and changes in amylin secretion in response to therapies may influence the rate of production of islet amyloid. The primary objective of this study was to determine whether therapy with sulfonylurea or basal insulin in NIDDM would alter amylin secretion in a way that might affect the formation of islet amyloid. RESEARCH DESIGN AND METHODS In a randomized crossover design, eight subjects with NIDDM underwent diree 8-week periods of therapy with diet alone, sulfonylurea, or exogenous basal insulin, with evaluation of amylin, amylin-like peptide (ALP), and glucose and C-peptide concentrations, both during fasting and after a standard breakfast. Changes in (β-cell function (%β) were assessed, in the basal state by homeostasis model assessment (HOMA) and in the stimulated state by hyperglycemic clamps. Seven nondiabetic control subjects each underwent a meal profile and hyperglycemic clamp. RESULTS Both sulfonylurea and insulin therapy reduced basal glucose concentrations compared with diet alone, but neither reduced the increased postprandial glucose increments. Both sulfonylurea and insulin therapy increased basal %β, assessed by HOMA, but only sulfonylurea increased the second-phase C-peptide responses to the hyperglycemic clamp. Sulfonylurea increased time-averaged mean postprandial amylin and ALP concentrations compared with diet alone (geometric mean [1-SD range] for amylin, 4.9 [2.0–11.8] vs. 3.0 [1.4–6.2] pmol/1, P = 0.003; for ALP, 16.4 [8.5–31.7] vs. 10.1 [4.9–20.8] pmol/1, P = 0.001). Insulin therapy reduced basal ALP concentrations compared with diet alone (2.9 [1.5–5.6] vs. 6.0 [2.6–13.6] pmol/1, P = 0.03), but had no effect on postprandial concentrations of amylin (3.0 [1.3–6.5] pmol/1) or ALP (10.0 [5.5–18.1] pmol/1). CONCLUSIONS By increasing postprandial concentrations of the constituent peptides of islet amyloid, sulfonylurea therapy might increase the rate of deposition of islet amyloid and thereby accelerate the decline of %β in NIDDM, compared with diet therapy alone.

Safety of antipsychotics in people with intellectual disability

BACKGROUND Despite frequent use, little is known about the metabolic and endocrine side-effects of antipsychotics in individuals with intellectual disability. AIMS To compare indices of obesity, glucose, lipids and prolactin between antipsychotic-treated and antipsychotic-naive individuals with intellectual disability and also between participants with intellectual disability and controls from the general population. METHOD Observational study comparing 138 antipsychotic-treated and 64 antipsychotic-naive participants with intellectual disability in one National Health Service trust with general population controls. RESULTS Antipsychotic treatment comprised: risperidone 48%,olanzapine 18%, thioxanthenes 10%, other 24%; monotherapy 95% of participants; mean treatment duration 8 years;median daily chlorpromazine equivalent dose 108 mg(range 16–667). Metabolic indices were the same or more favourable in the intellectual disability group than the general population control group but overweight/obesity and type 2 diabetes were more prevalent in the women in the intellectual disability group than the control group. Metabolic indices were similar, statistically or clinically, between the antipsychotic-treated and the antipsychotic-naive groups but there was a non-significant trend towards a higher rate of type 2 diabetes in the antipsychotic group. A total of 100%and 70% of participants on amisulpride/sulpiride and risperidone respectively had hyperprolactinaemia, with secondary hypogonadism in 77% and 4% of affected women and men. CONCLUSIONS Antipsychotics, on average, did not increase metabolic risk,although the existence of a susceptible subgroup at risk of diabetes cannot be excluded. Some antipsychotics induced hyperprolactinaemic hypogonadism, requiring active management. However, our findings suggest that antipsychotics at the low doses routinely prescribed for people with intellectual disability are generally safe in relation to metabolic adverse effects, even if efficacy remains poorly defined.

Evaluation of Serum 1,5 Anhydroglucitol Levels as a Clinical Test to Differentiate Subtypes of Diabetes

OBJECTIVE Assignment of the correct molecular diagnosis in diabetes is necessary for informed decisions regarding treatment and prognosis. Better clinical markers would facilitate discrimination and prioritization for genetic testing between diabetes subtypes. Serum 1,5 anhydroglucitol (1,5AG) levels were reported to differentiate maturity-onset diabetes of the young due to HNF1A mutations (HNF1A-MODY) from type 2 diabetes, but this requires further validation. We evaluated serum 1,5AG in a range of diabetes subtypes as an adjunct for defining diabetes etiology. RESEARCH DESIGN AND METHODS 1,5AG was measured in U.K. subjects with: HNF1A-MODY (n = 23), MODY due to glucokinase mutations (GCK-MODY, n = 23), type 1 diabetes (n = 29), latent autoimmune diabetes in adults (LADA, n = 42), and type 2 diabetes (n = 206). Receiver operating characteristic curve analysis was performed to assess discriminative accuracy of 1,5AG for diabetes etiology. RESULTS Mean (SD range) 1,5AG levels were: GCK-MODY 13.06 μg/ml (5.74–29.74), HNF1A-MODY 4.23 μg/ml (2.12–8.44), type 1 diabetes 3.09 μg/ml (1.45–6.57), LADA 3.46 μg/ml (1.42–8.45), and type 2 diabetes 5.43 (2.12–13.23). Levels in GCK-MODY were higher than in other groups (P < 10−4 vs. each group). HNF1A-MODY subjects showed no difference in unadjusted 1,5AG levels from type 2 diabetes, type 1 diabetes, and LADA. Adjusting for A1C revealed a difference between HNF1A-MODY and type 2 diabetes (P = 0.001). The discriminative accuracy of unadjusted 1,5AG levels was 0.79 for GCK-MODY versus type 2 diabetes and 0.86 for GCK-MODY versus HNF1A-MODY but was only 0.60 for HNF1A-MODY versus type 2 diabetes. CONCLUSIONS In our dataset, serum 1,5AG performed well in discriminating GCK-MODY from other diabetes subtypes, particularly HNF1A-MODY. Measurement of 1,5AG levels could inform decisions regarding MODY diagnostic testing.

Identification of a Novel β-Cell Glucokinase (GCK) Promoter Mutation (−71G>C) That Modulates GCK Gene Expression Through Loss of Allele-Specific Sp1 Binding Causing Mild Fasting Hyperglycemia in Humans

OBJECTIVE Inactivating mutations in glucokinase (GCK) cause mild fasting hyperglycemia. Identification of a GCK mutation has implications for treatment and prognosis; therefore, it is important to identify these individuals. A significant number of patients have a phenotype suggesting a defect in glucokinase but no abnormality of GCK. We hypothesized that the GCK β-cell promoter region, which currently is not routinely screened, could contain pathogenic mutations; therefore, we sequenced this region in 60 such probands. RESEARCH DESIGN AND METHODS The β-cell GCK promoter was sequenced in patient DNA. The effect of the identified novel mutation on GCK promoter activity was assessed using a luciferase reporter gene expression system. Electrophoretic mobility shift assays (EMSAs) were used to determine the impact of the mutation on Sp1 binding. RESULTS A novel −71G>C mutation was identified in a nonconserved region of the human promoter sequence in six apparently unrelated probands. Family testing established cosegregation with fasting hyperglycemia (≥5.5 mmol/l) in 39 affected individuals. Haplotype analysis in the U.K. family and four of the Slovakian families demonstrated that the mutation had arisen independently. The mutation maps to a potential transcriptional activator binding site for Sp1. Reporter assays demonstrated that the mutation reduces promoter activity by up to fourfold. EMSAs demonstrated a dramatic reduction in Sp1 binding to the promoter sequence corresponding to the mutant allele. CONCLUSIONS A novel β-cell GCK promoter mutation was identified that significantly reduces gene expression in vitro through loss of regulation by Sp1. To ensure correct diagnosis of potential GCK-MODY (maturity-onset diabetes of the young) cases, analysis of the β-cell GCK promoter should be included.

Use of focus groups to develop methods to communicate cardiovascular disease risk and potential for risk reduction to people with type 2 diabetes

BACKGROUND People need to perceive a risk in order to build an intention-to-change behaviour yet our ability to interpret information about risk is highly variable. OBJECTIVES We aimed to use a user-centred design process to develop an animated interface for the UK Prospective Diabetes Study (UKPDS) Risk Engine to illustrate cardiovascular disease (CVD) risk and the potential to reduce this risk. In addition, we sought to use the same approach to develop a brief lifestyle advice intervention. METHODS Three focus groups were held. Participants were provided with examples of materials used to communicate CVD risk and a leaflet containing a draft brief lifestyle advice intervention and considered their potential to increase motivation-to-change behaviours including diet, physical activity, and smoking in order to reduce CVD risk. Discussions were tape-recorded, transcribed and coded and recurring themes sought. RESULTS Sixty-two percent of participants were male, mean age was 66 years (range = 47-76 years) and median age at leaving full-time education was 18 years (range = 15-40 years). Sixteen had type 2 diabetes and none had a prior history of CVD. Recurring themes from focus group discussions included the following: being less numerate is common, CVD risk reduction is important and a clear visual representation aids comprehension. CONCLUSION A simple animated interface of the UKPDS Risk Engine to illustrate CVD risk and the potential for reducing this risk has been developed for use as a motivational tool, along with a brief lifestyle advice intervention. Future work will investigate whether use of this interactive version of the UKPDS Risk Engine and brief lifestyle advice is associated with increased behavioural intentions and changes in health behaviours designed to reduce CVD risk.

Availability of Type II Diabetic Families for Detection of Diabetes Susceptibility Genes

Type II diabetes is a familial disorder, as evidenced by the increased prevalence in monozygotic cotwins and first-degree relatives of affected subjects; however, its genetic etiology is largely unknown. Well-characterized pedigrees are an essential resource for the study of susceptibility genes for type II diabetes. This study describes a 5-yr search for type II diabetic families in Oxfordshire, U.K. We interviewed 950 type II diabetic subjects concerning the availability of first-degree relatives; 127 Caucasian families ascertained through a proband with type II diabetes were studied, and 589 first-degree relatives were characterized. Three large pedigrees with maturity-onset diabetes of the young, and 8 multiplex multigenerational type II diabetic pedigrees were identified. We identified 12 sib-pairs in which both siblings had type II diabetes; however, only 7 sib-pairs had both parents alive, and 2 of these had both parents affected. If one also considers one sib having diabetes and one sib having glucose intolerance as being an affected sib-pair, we identified 30 sib-pairs of which 7 had both parents affected and probably had bilineal inheritance. We identified 76 complete nuclear families with both parents and offspring available for study, but only 6 were of optimal structure for linkage analysis. In conclusion, multiplex pedigrees and type II diabetic sib-pairs with living parents are uncommon, and their ascertainment requires a substantial investment of resources. Large-scale collaborative multicenter initiatives would be needed to collect a large resource of family material for the study of susceptibility genes for type II diabetes.

Perceptions of heart attack risk amongst individuals with diabetes

AIM Individuals with diabetes are at increased risk of cardiovascular disease (CVD). There is good evidence that this risk can be reduced by pharmacotherapies and lifestyle modification. Despite this, knowledge of CVD risk amongst individuals with diabetes remains poor. We undertook a qualitative study to investigate lay perceptions of heart attack risk amongst individuals with diabetes in order to gather information about underlying perceptions concerning risk and risk reduction strategies. METHODS We conducted three focus groups in Oxford using an open-ended question map. Content analysis was performed to identify recurring themes, similar patterns, distinctions and supportive quotations. RESULTS Concern about having a heart attack varied widely. A commonly held view was that a 10-year heart attack risk of 10% or greater was high and being aware of ones risk was important so that lifestyle changes or other interventions could be implemented. Participants consistently viewed physical activity as potentially harmful. Almost all participants sought healthcare and lifestyle advice from their primary healthcare providers in the first instance, preferring this to information in the lay press or government campaigns. CONCLUSION The focus groups have allowed us to better understand lay perceptions of, and underlying assumptions about, CVD risk. These findings may be of use when discussing CVD risk and risk reduction strategies in primary care.