The impact of a family history of Type II (non-insulin-dependent) diabetes mellitus on the risk of diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus

Aims/hypothesis. There is substantial evidence for a role of genetic factors in the development of diabetic nephropathy. In Pima Indians, a link between susceptibility to diabetic nephropathy and Type II (non-insulin-dependent) diabetes mellitus has been proposed. In this study, our aim was to examine the association between a family history of Type II diabetes and diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus. Methods. In a cross-sectional case-control study, we assessed the prevalence of Type II diabetes in the parents of 137 Type I diabetic patients with diabetic nephropathy (albuminuria > 300 μg/min in two of three overnight urine collections) compared with the parents of 54 Type I diabetic patients without nephropathy (albuminuria < 20 μg/min). Results. Thirty-four (25 %) of the patients with nephropathy compared with five (9 %) of the patients without nephropathy had a parental history of Type II diabetes (p = 0.019). A parental history of Type II diabetes was associated with a three-fold risk [odds ratio 2.95 (95 % confidence interval: 1.03 to 8.40), p = 0.043] of diabetic nephropathy after adjustment for sex, glycaemic control and family history of hypertension. Furthermore, there was an excess of risk factors for development of Type II diabetes (higher fasting plasma glucose concentrations, higher prevalence of hypertension, higher waist-hip ratio and a tendency towards more glucose intolerance) among previously non-diabetic parents of patients with nephropathy. Conclusion/interpretation. Genetic or environmental factors or both related to familial Type II diabetes increase susceptibility to diabetic nephropathy in patients with Type I diabetes. [Diabetologia (1999) 42: 519–526] Received: 30 September 1998 and in final revised form: 28 December 1998     

Tumour-induced hypoglycaemia in a patient with insulin-dependent diabetes mellitus

We report on a case of malignant insulinoma occurring in a patient with genuine insulin-dependent diabetes mellitus (IDDM). A review of cases concerning patients with diabetes mellitus and insulinomas is presented, and reveals only patients with non-insulin-dependent diabetes mellitus (NIDDM). Our case appears to be the first in showing the combination of IDDM and a functioning malignant insulinoma.     

Behaviors predicting foot lesions in patients with non-insulin-dependent diabetes mellitus

Associations between specific foot-care behaviors and foot lesions in patients with non-insulin-dependent diabetes mellitus were prospectively investigated. Data from a randomized controlled trial for preventing diabetic foot lesions were analyzed as a prospective cohort using logistic regression. Independent variables included foot-care behaviors, patient self-foot examination, going barefoot, availability of foot-care assistance, and visits to health-care providers. The dependent variable was a foot wound on each foot at follow-up. In the final multivariate model, patients who rarely lubricated their feet had an increased risk of foot lesions. Increasing patient use of emollients may be key to preventing foot lesions.     

A multinational study of the effects of low-dose pravastatin in patients with non-insulin-dependent diabetes mellitus and hypercholesterolemia

This multinational, 16-week, randomized, doubleblind, placebo-controlled study evaluated the efficacy and safety of low-dose pravastatin in 325 patients with non-insulindependent diabetes mellitus (NIDDM) and hypercholesterolemia [serum total cholesterol concentrations of 5.2-7.8 mmol/1 (200 to 300 mg/dl)]. Patients were randomized to receive pravastatin 10 mg or matching placebo with doubling of the dose after 8 weeks if predefined target levels for total cholesterol [(i.e., < 5.2 mmol/1 (200 mg/dl) or > 15% decrease from baseline] had not been achieved. At Week 16, pravastatin-treated patients showed a 21.4% decrease in serum low-density lipoprotein cholesterol (LDL-C) and a 13.5% reduction in serum total cholesterol (TC) concentrations (p < 0.001 compared with placebo). Levels of triglycerides (TG) were reduced 9.6% during pravastatin treatment (p < 0.05 compared with placebo) while high-density lipoprotein cholesterol (HDL-C) levels were increased 4.4% (p =NS). Adverse events and laboratory test abnormalities were similar among patients treated with pravastatin or placebo. Glycosylated hemoglobin (HbA₁C) levels remained unchanged. The results of this study demonstrate that low-dose pravastatin is effective and well tolerated for lowering elevated cholesterol concentrations during short-term treatment of patients with NIDDM and hypercholesterolemia.     

Factors associated with basal metabolic rate in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary To examine determinants of basal metabolic rate we studied 66 Type 2 (non-insulin-dependent) diabetic and 24 healthy age- and weight-matched control subjects with indirect calorimetry and infusion of [³H-3-] glucose. Eight Type 2 diabetic patients were re-studied after a period of insulin therapy. Basal metabolic rate was higher in Type 2 diabetic patients than in control subjects (102.8 ± 1.9 J · kg LBM^–1-min^–1 vs 90.7 ± 2.8 J · kg LBM^–1;min^–1; p<0.01) and decreased significantly with insulin therapy (p <0.01). The basal rate of hepatic glucose production was higher in Type 2 diabetic patients than in control subjects (1044.0 ± 29.9 vs 789.3 ± 41.7 mol/min; p <0.001) and decreased after insulin therapy (p <0.01). Hepatic glucose production correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.49; p <0.001) and in control subjects (r = 0.50; p<0.05). Lipid oxidation was increased in Type 2 diabetic patients compared with control subjects (1.68 ± 0.05 vs 1.37 ± 0.08 mol · kg LBM^–1 · min^–1'; p <0.01) and decreased significantly after insulin therapy (p <0.05). The rate of lipid oxidation correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.36; p <0.01) and in control subjects (r = 0.51; p <0.01). These data demonstrate that basal metabolic rate, rates of hepatic glucose production and lipid oxidation are interrelated in Type 2 diabetic patients. A reduction of the hepatic glucose production, however, is associated with a reduction in lipid oxidation, which in turn, may result in a reduction in basal metabolic rate.     

Shared genetic susceptibility of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus: contributions of HLA and haptoglobin

Summary Epidemiologic data suggest that having a parent with Type 2 (non-insulin-dependent) diabetes mellitus increases the risk for Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 diabetes and Type 2 diabetes. We contrast genetic risk factors in three sets of families, consisting of (1) a single Type 1 diabetic child (proband) and non-diabetic parents, (2) multiple Type 1 diabetic siblings and non-diabetic parents, and (3) at least one Type 1 diabetic child and at least one Type 2 diabetic parent. Previous studies have demonstrated that HLA region genes, which elevate the risk in Type 1 diabetes, have no significant effect with respect to the risk for developing Type 2 diabetes. An earlier report cited a contribution by the haptoglobin locus to genetic susceptibility for Type 2 diabetes. We provide evidence that a high risk HLA antigen (HLA-DR3) is decreased to a greater extent in Type 1 patients with a Type 2 parent than in Type 1 patients in which the parents are not diabetic. The role of HLA-DR4 is maintained in these families, with an unexpectedly significant increased rate of transmission of the HLA-DR4 allele from Type 2 parent to Type 1 offspring. The role of haptoglobin in these families does not appear to be important, either with respect to association with diabetes or with respect to linkage with a secondary susceptibility locus. These results indicate that families with a Type 2 parent and Type 1 child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility.     

Primary prevention of Type 2 (non-insulin-dependent) diabetes mellitus

Summary Type 2 (non-insulin-dependent) diabetes mellitus is the major form of the disease in all societies. Its public health impact appears to be increasing and the greatest genetic predisposition to the disease is encountered in developing communities. The reduction or elimination of disease in whole populations is a fundamental goal in public health. Whilst several factors are associated with the development of Type 2 diabetes, it is not clear how they cause the disease, if indeed they do, nor whether they act in the same way in all populations. Risk factors may be true determinants of a disease but alternatively they may be associated with its occurrence only by virtue of an innocent relationship with the true causes. Furthermore, known risk factors usually explain only a small proportion of any chronic disease. The role of risk factors in disease causation is therefore of fundamental importance in considering disease prevention. Two alternative strategies for prevention of disease in populations have been proposed. The population strategy seeks to remove the causes of disease in communities as a whole, whilst the high-risk strategy aims to identify subjects at increased risk, and to intervene selectively. The population approach should be tried and carefully evaluated in selected communities at above-average risk of several noncommunicable diseases. However, certain epidemiological features of Type 2 diabetes, including the distributional characteristics of glycaemia and the complications of hyperglycaemia, the clustering of cardiovascular risk factors in the diabetic subpopulation, as well as uncertainties over the causal nature of known risk factors, suggest that a high-risk approach to prevention is also appropriate. Optimal allocation of resources to the two approaches requires a detailed knowledge of the disease process in individual communities.     

Insulin resistance and mechanical dysfunction in hearts of Wistar rats with streptozotocin-induced non-insulin-dependent diabetes mellitus

Summary The present study correlates the insulin resistance seen in the myocardium of rats with streptozotocin-induced non-insulin-dependent diabetes mellitus with insulin secretory defects, hyperglycaemia and disease duration. Two-day-old male Wistar rats were given a bolus injection of streptozotocin (0.09 mg/g body weight) which caused glucose intolerance when these animals reached adulthood. Although these rats developed a progressive resistance to the actions of insulin in the heart this did not correlate with the development of glucose intolerance. However, a correlation was seen with a shift in insulin secretory response from hyper- to hypo-secretion which developed between 6 and 14 months of age. Moreover, this shift in secretory pattern can be associated with the onset of a cardiac mechanical malfunction.     

Albuminuria in Type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance in Pima Indians

Summary The prevalence of abnormal urinary albumin excretion, defined by a urine albumin to creatinine ratio>-30 mg/g (approximately equivalent to an albumin excretion rate of >-30 mg/24 h), was determined in 2728 Pima Indians aged >-15 years from the Gila River Indian Community in Arizona, a population with a high prevalence of Type 2 (non-insulin-dependent) diabetes mellitus. Excessive albumin excretion was present in 8% of subjects with normal glucose tolerance, 15% of those with impaired glucose tolerance, and 47% of subjects with diabetes. The intermediate prevalence of abnormal albuminuria in those with impaired glucose tolerance suggests that hyperglycaemia even at levels below those diagnostic of diabetes is associated with renal abnormalities in some subjects and that these abnormalities may precede the onset of diabetes. Abnormal albuminuria at levels not reliably detected by the usual dipstick methods was commonly observed in Pima Indians with diabetes, even those with diabetes of recent onset. Associations were found with age, duration of diabetes, level of glycaemia, blood pressure, and treatment with insulin.     

Mutation in the mitochondrial tRNAleu at position 3243 and spontaneous abortions in Japanese women attending a clinic for diabetic pregnancies

Summary Mitochondrial DNA is exclusively maternally inherited. We recently found the prevalence of diabetic patients with an A to G transition at position 3243 of leucine tRNA (3243 base pair (bp) mutation) to be nearly 1 % in randomly selected Japanese subjects. Here, we report the higher prevalence of diabetic patients with the 3243 bp mutation in a specific Japanese population of women attending a diabetic pregnancy clinic. Of 102 patients with non-insulin-dependent diabetes mellitus 6 (5.9 %) were positive for the mutation, 1 (8.3 %) of 12 patients with gestational diabetes and 2 (5.9 %) out of 34 borderline diabetic patients. In contrast, none of 64 patients (0 %) with insulin-dependent diabetes mellitus had the 3243 bp mutation. Moreover, there was a difference in the prevalence of spontaneous abortions between patients with and without this mutation (27.3 vs 12.4 %). Among nine probands with the mutation, four had a history of one spontaneous abortion (p = 0.0518) and two had a history of two abortions (p = 0.0479). Two probands had a spontaneous abortion even while under strict diabetic metabolic control. The 3243 bp mutation thus may cause spontaneous abortion during pregnancy. [Diabetologia (1995) 38: 809–815] Received: 24 August 1994 and in revised form: 29 December 1994     

Metabolic characteristics of autoimmune diabetes mellitus in adults

Summary It is still a matter of debate whether patients who develop islet-cell antibody positive autoimmune diabetes during adulthood represent slowly evolving Type 1 (insulindependent) diabetes mellitus or a separate subgroup of Type 2 (non-insulin-dependent) diabetes. To address this question, we measured C-peptide response to a test meal, and energy metabolism in the basal state and during a euglycaemic, hyperinsulinaemic clamp in (1) 29 patients with Type 2 diabetes; (2) 10 patients with autoimmune diabetes developing after the age of 40 years; (3) 11 patients with Type 1 diabetes and (4) 15 non-diabetic control subjects. While C-peptide response to a test meal was lacking in Type 1 diabetes and nearly normal in Type 2 diabetes, the C-peptide response in autoimmune diabetes was markedly reduced. Patients with Type 2 diabetes, autoimmune diabetes and Type 1 diabetes showed a 47%, 45% and 42%, respectively, reduction in the rate of non-oxidative glucose metabolism compared with control subjects (p<0.05-0.01). Similarly, patients with Type 2 diabetes (+52%), autoimmune diabetes (+27%) and Type 1 diabetes (+33%) presented with an enhanced basal rate of hepatic glucose production, which was less suppressed by insulin compared with healthy control subjects (p<0.01). However, patients with autoimmune diabetes derived more energy from oxidation of glucose and proteins and less energy from oxidation of lipids than patients with either Type 1 or Type 2 diabetes (p<0.05-0.01). In conclusion, patients who develop autoimmune diabetes during adulthood share the defects in hepatic glucose production and in non-oxidative glucose metabolism with both Type 1 and Type 2 diabetes. Oxidative energy metabolism in autoimmune diabetes, however, differs from that observed in Type 1 and Type 2 diabetes. Given the metabolic characteristics of these patients, it seems justified to consider autoimmune diabetes in adults as a subgroup of diabetes developing in adult age.     

Five-year follow-up of islet cell antibodies in Type 2 (non-insulin-dependent) diabetes mellitus

Summary The aim was to study the frequency and appearance of cytoplasmic islet cell antibodies in relation to impairment of insulin secretory capacity and some clinical characteristics in a representative group of middle-aged (45–64 years) patients with Type 2 (non-insulin-dependent) diabetes mellitus (70 male, 63 female) at the time of diagnosis and at five-year follow-up. Non-diabetic control subjects (62 male, 82 female) were similarly examined at five-year intervals. At the baseline five out of 133 (3.8%) diabetic patients were positive for conventional and four (3.0%) for complement-fixing islet cell antibodies. Ten patients had become positive by the second screening for conventional antibodies and six for complement-fixing antibodies, but none showed negative conversion. Two non-diabetic subjects (1.5%) became antibody positive during the follow-up. Insulin treatment was started during the follow-up for four out of 15 (27%) conventional antibody positive and for one out of 121 (0.8%) antibody negative diabetic patients (p=0.001). The sensitivity of the positive conventional and complement-fixing antibody for identifying patients who developed an impairment of insulin secretory capacity (post-glucagon C-peptide 0.60nmol/l at 5-year) was 75%. The respective specificity was 90% and the positive predictive values were highest in the case of high positivity (50%). The negative predictive value of antibody positivity was close to 100%. In conclusion, islet cell antibody positivity in patients classified as Type 2 was persistent during the follow-up and predicted the future development of insulin deficiency especially in those patients with high or increasing antibody titres.     

Insulin resistance,hypertension and microalbuminuria in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary We examined the impact of hypertension and microalbuminuria on insulin sensitivity in patients with Type 2 (non-insulin-dependent) diabetes mellitus using the euglycaemic insulin clamp technique in 52 Type 2 diabetic patients and in 19 healthy control subjects. Twenty-five diabetic patients had hypertension and 19 had microalbuminuria. Hypertension per se was associated with a 27% reduction in the rate of total glucose metabolism and a 40% reduction in the rate of non-oxidative glucose metabolism compared with normotensive Type 2 diabetic patients (both p<0.001). Glucose metabolism was also impaired in normotensive microalbuminuric patients compared with normotensive normoalbuminuric patients (29.4±2.2 vs 40.5±2.8 mol · kg lean body mass^–1 · min^–1; p=0.012), primarily due to a reduction in non-oxidative glucose metabolism (12.7±2.9 vs 21.1±2.6 mol · kg lean body mass^–1 ·min^–1; p=0.06). In a factorial ANOVA design, however, only hypertension (p=0.008) and the combination of hypertension and microalbuminuria (p=0.030) were significantly associated with the rate of glucose metabolism. The highest triglyceride and lowest HDL cholesterol concentrations were observed in Type 2 diabetic patients with both hypertension and microalbuminuria. Of note, glucose metabolism was indistinguishable from that in control subjects in Type 2 diabetic patients without hypertension and microalbuminuria (40.5±2.8 vs 44.4±2.8 mol · kg lean body mass^–1 · min^–1). We conclude that insulin resistance in Type 2 diabetes is predominantly associated with either hypertension or microalbuminuria or with both.     

Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family

Summary Mutations were screened for in the glucokinase gene of 25 Japanese patients with Type 2 (non-insulin-dependent) diabetes mellitus. Each exon was scanned by electrophoresis of enzymatically amplified DNA segments under non-denaturing conditions and variants were sequenced. A variant pattern was detected in exon 5 of one patient. Direct sequencing of this exon revealed a single nucleotide substitution in codon 188 (GCTACT) of one of two alleles resulting in the mutation of Ala¹⁸⁸Thr, an invariant residue in the sequence of all mammalian glucokinases and hexokinases. This mutation was not found in 40 normal control subjects. The proband had been diagnosed with Type 2 diabetes at the age of 62 years. Four other members of her family have the same mutation and all have Type 2 diabetes or impaired glucose tolerance. The youngest age at diagnosis of Type 2 diabetes in these other members was 13 years, suggesting that her pedigree was maturity-onset diabetes of the young (MODY). All subjects with the Thr¹⁸⁸ mutation show a decreased insulin secretory response during oral glucose tolerance testing. Mutations in the glucokinase gene associated with Type 2 diabetes have been previously identified in Caucasian (French and British) subjects. This study indicates that mutations in this gene are also implicated in the development of Type 2 diabetes in Asians. Further studies are required to determine the frequency of mutations in glucokinase among Japanese patients with Type 2 diabetes.     

糖尿病患者血清生长激素与肌酐清除率

测定了１６例胰岛素依赖型糖尿病（ＩＤＤＭ）患者，１９例非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者和２３例对照者的血清生长激素（ＧＨ）水平。在ＩＤＤＭ组，无论是肌酐清除率（Ｃｃｒ）正常或减低，其ＧＨ值均为２．５３±１．７３μｇ／Ｌ，均高于对照组的０．７１±０．５３μｇ／Ｌ（Ｐ＜０．０５），ＧＨ与Ｃｃｒ呈负相关（ｒ＝０．６３，Ｐ＜０．０１），ＮＩＤＤＭ组Ｃｃｒ＜５０ｍｌ／ｍｉｎ者ＧＨ值为１．８３±０．４７μｇ／Ｌ显著高于对照组（Ｐ＜０．０５）和Ｃｃｒ＞８０ｍｌ／ｍｉｎ组（ＧＨ０．８３±０．４９μｇ／Ｌ，Ｐ＜０．０５）。糖尿病（ＤＭ）伴微血管并发症者，ＧＨ值为２．９２±１．７０μｇ／Ｌ，高于无此并发症者ＧＨ１．２４±０．９７μｇ／Ｌ，（Ｐ＜０．０１），认为ＧＨ与ＤＭ微血管并发症有关。     

HLA-associated susceptibility to Type 2 (non-insulin-dependent) diabetes mellitus: the Wadena City Health Study

Summary Epidemiologic data suggest that a parental history of Type 2 (non-insulin-dependent) diabetes mellitus increases the risk of Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 and Type 2 diabetes. We have previously reported evidence that HLA-DR4-linked factors may represent a homogeneous subset of diabetes susceptibility. First, HLA-DR4 frequency was higher in Type 1 diabetic study subjects with a Type 2 diabetic parent than in Type 1 diabetic subjects whose parents were not diabetic. Second, a DR4-haplotype was transmitted from the Type 2 diabetic parent to the Type 1 offspring more often than expected. These data are consistent with the hypothesis that families with a Type 2 diabetic parent and Type 1 diabetic child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility. In this report, we further explore the relationship between the high-risk HLA antigen (HLA-DR4) in study subjects with differing glycaemic status (National Diabetes Data Group criteria). In this community-based study, we find evidence that HLA-DR4 is increased in study subjects with Type 2 diabetes and may be a marker for Type 2 diabetes susceptibility.     

Impact of initial treatment on renal function in newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus

Summary The impact of improved glycaemic control on renal function in newly-presenting Type 2 (non-insulin-dependent) diabetic patients has not been adequately researched. Consequently, glomerular filtration rate and effective renal plasma flow and urinary albumin excretion rates were determined in 76 subjects (age (mean (SD)): 54 (9.5) years; 50 male) of an original cohort of 110 newly-presenting normotensive non-proteinuric Type 2 diabetic patients following 6 months treatment with diet alone (n=42) or with oral hypoglycaemic agents (n=34). Significant reductions were observed in (presentation vs 6 months): body mass index (p<0.01); fasting plasma glucose (p<0.001); glycated haemoglobin (HbA₁) (p<0.001); systolic blood pressure (p<0.01); and diastolic blood pressure (p<0.001). Glomerular filtration rate declined from 117 (22) to 112 (21) ml·min^–1 (p<0.01), with unchanged effective renal plasma flow (534 (123) vs 523 (113) ml·min^–1) and filtration fraction (22.4 (3.0) vs 21.8 (3.4)%). Albumin excretion rate (median (range)) declined from 1.1 (0.1–34.7) to 0.5 (0.1–29.9) g·min^–1 (p<0.01). Changes in glomerular filtration rate ( values) were inversely correlated with presentation values (p<0.001), and positive relationships were observed with effective renal plasma flow (p<0.01), and glycated haemoglobin (p<0.05). Type 2 diabetic patients with glomerular filtration rate values at presentation over 120 ml·min^–1 demonstrated significant reduction in glomerular filtration rate (n=31; p<0.001), whilst those with original values less than 120 ml·min^–1 remained unchanged (n=45). Glomerular filtration rate, effective renal plasma flow and filtration fraction for the Type 2 diabetic patients remained elevated compared with age-controlled normal subjects (p<0.01-0.001). Albumin excretion rate at presentation and 6 months were positively correlated with fasting plasma glucose levels (p<0.05) but not renal haemodynamics. Thus, glomerular filtration rate and albumin excretion rate in newly-presenting Type 2 diabetic patients are influenced by metabolic control. Improved glycaemia for 6 months produces a reduction in glomerular filtration rate, mainly in the younger patients with values greater than 120 ml·min^–1 at diagnosis of diabetes. Despite these changes, renal haemodynamic parameters remain elevated compared with age-matched normal subjects.     

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

Summary Nuclear 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 (5.5fpg<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.Abbreviations IGT Impaired glucose tolerance - GTT glucose tolerance test - NIDDM non-insulin-dependent diabetes mellitus - fpg fasting plasma glucose - apg achieved plasma glucose - CIGMA continuous infusion of glucose test - BMI body mass index