Family History Of Non-insulin-dependent Diabetes Mellitus Research Articles

Clinical characteristics of non-insulin-dependent diabetes mellitus among southwestern American Indian youths.

The clinical characteristics and presentation of non-insulin-dependent diabetes mellitus (NIDDM) among 22 youths, aged less than 20 years, of an American Indian tribe Tohono O'odham Nation in the southwestern United States were studied. Ten males and 12 females (7-20 years old) were identified with a 13.7-year mean age of onset of diabetes. Over 80% (18/22) of the patients were obese at diagnosis having a body mass index greater than the 95th percentile for their age and sex, and there was a strong family history of NIDDM; eight patients were born to mothers who had gestational diabetes, and 19 patients had at least one parent with NIDDM. At the time of diagnosis, plasma glucose levels ranged from 10.3 mmol/L to 33 mmol/L, with nearly 60% (13/22) of the patients having a glucose reading greater than 16.8 mmol/L. C-peptide levels were done on 10 patients, and these were in the normal to elevated range. Clinical management of the 22 patients varied. To control hyperglycaemia and symptoms, such as nocturia and polyuria, 14 patients were on oral hypoglycaemic medication, and five were on insulin therapy. Compliance with dietary management was very difficult for these patients as evidenced by the fact that only three patients were on dietary control for their diabetes. The cases described in this series demonstrate NIDDM in childhood and illustrate the importance of accurate classification of diabetes during childhood, particularly in children from populations at high risk for NIDDM.

Peripheral tissue glucose uptake is not reduced after an oral glucose load in Southern Italian subjects at risk of developing non-insulin-dependent diabetes mellitus

Studies searching for the inherited defects that cause non—insulin-dependent diabetes mellitus (NIDDM) have been performed mostly in Northern European subjects using the hyperinsulinemic clamp technique. The conclusion drawn from most of these studies is that peripheral insulin resistance is likely a primary inherited defect. Our aim was to examine early defects in glucose metabolism using a more physiological technique in a different ethnic group. For this, a double-label oral glucose tolerance test (OGTT) was performed in young diabetes-prone Southern Italian subjects who had both parents with NIDDM (relatives) and in subjects with no family history of NIDDM (matched for age, weight, and ethnicity). Fasting plasma glucose and insulin in the relatives were normal; however, they had impaired glucose tolerance during the OGTT. This was due to reduced hepatic glucose uptake (17.9 ± 2.8 v 28.1 ± 2.3 g, P < .02). No defects were found in the metabolic clearance rate (MCR) of glucose or endogenous glucose production. During an intravenous glucose tolerance test (IVGTT), insulin sensitivity was again found to be normal (3.04 ± 0.65 in relatives v 2.33 ± 0.38 min −1 per μmol · L −1 · min in controls), with a marked reduction in first-phase insulin secretion in the relatives (110 ± 12 v 211 ± 18 pmol · L −1 · min per mmol · L −1, P < .001). A strong correlation was found between hepatic glucose uptake and insulin secretion ( r = .81, P < .001), which may suggest that the same abnormality operates in both the liver and pancreas. Therefore, the metabolic defect that causes hyperglycemia in diabetes-prone subjects is not always a reduced peripheral insulin sensitivity. The genetic basis of NIDDM may differ between different ethnic groups.

High prevalence of abnormal glucose tolerance and metabolic disturbances in first degree relatives of NIDDM patients.: A study in Catalonia, a mediterranean community

Our study aimed to analyse clinical and metabolic characteristics of first degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) in Catalonia. Two hundred and five subjects (39.8±14.2 year-old, 61% women) were included in the study. An oral glucose tolerance test (OGTT) was performed, obtaining basal plasma glucose and insulin, in order to calculate, %B (HOMA β cell function) and %S (HOMA insulin sensitivity). A 30.7% of subjects showed an abnormal glucose tolerance, either as impaired glucose tolerance (IGT) (20.5%) or as NIDDM (10.2%). Glycaemia after the OGTT (120 min) was independently determined by fasting glycaemia and age ( R 2=0.50; P<0.001). As expected, subjects with normal glucose tolerance (NGT) were significantly younger than IGT and NIDDM subjects. The relatives with IGT and NIDDM display more features of syndrome-X when compared to NGT. Likewise, NGT relatives were less insulin sensitive and their basal insulin levels were higher when compared with a control group of subjects without familial history of NIDDM (log %S, 3.6±0.4 vs. 3.9±0.4; P=0.000; log-insulin 2.4±0.4 vs. 2.1±0.6 mU/l; P<0.02). In comparison with the general population, of any age group, NIDDM and IGT were more common in those subjects with a family history of NIDDM. Interestingly, the rates of abnormal glucose tolerance in the 55–64 and >64 year groups in the general population were similar to those seen in relatives two decades younger. Our study not only confirms a high prevalence of impaired glucose tolerance (IGT and NIDDM) in subjects with a family history of NIDDM, but also that these abnormalities can be detected at a very early age. Globally, this piece of information corroborates that special attention and precocious detection programs should be addressed to relatives of NIDDM patients.

Plasma amylin immunoreactivity and insulin resistance in insulin resistant relatives of patients with non-insulin-dependent diabetes mellitus.

To explore the potential relationship between concentrations of circulating amylin and the insulin resistance observed in first-degree relatives of patients with non-insulin-dependent-diabetes mellitus (NIDDM), we studied 40 relatives compared to 35 matched controls. Two newly developed immunoassays that measure either non-glycosylated or total amylin were applied. All subjects were examined by an oral glucose tolerance test (OGTT) and by a hyperinsulinemic euglycemic clamp (insulin infusion: 0.6 mU/kg/min). Glucose tolerance was normal in all, but insulin-stimulated glucose uptake (Rd) was diminished in the relatives (p < 0.001). Area under the curves (AUCs) during OGTT for plasma glucose (p < 0.01) and serum insulin (p=0.08), but not for plasma total and non-glycosylated amylin, were higher in relatives versus controls. In both groups, inverse correlations were found between Rd and AUC for plasma total and non-glycosylated amylin (p [all]<0.05). However, in multiple linear regression analyses, plasma total and non-glycosylated amylin failed to influence Rd independent of serum insulin and family history-of NIDDM. In conclusion, this study demonstrated inverse correlations between Rd and circulating concentrations of plasma total and non-glycosylated amylin in relatives and matched controls. These data, however, do not support the hypothesis that physiological amylin concentration are a major importance for the insulin resistance in relatives of NIDDM patients.

Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands.

No studies are available that have compared early defects in glucose metabolism in the offspring of insulin-deficient and insulin-resistant probands with non-insulin-dependent diabetes mellitus (NIDDM). To investigate this issue, we evaluated insulin secretion capacity with oral and intravenous glucose tolerance tests and with the hyperglycemic clamp, and insulin action with the euglycemic insulin clamp in 20 offspring of NIDDM patients with low fasting C-peptide (+/-450 pmol/liter), reflecting deficient insulin secretion (IS-group), 18 offspring of NIDDM patients with high fasting C-peptide (>/= 880 pmol/liter), reflecting insulin resistance (IR-group), and 14 healthy control subjects without a family history of NIDDM. The frequency of impaired glucose tolerance was 45.0% in the IS-group and 50% in the IR-group. The IS-group had lower insulin-glucose response at 30 min in the oral glucose tolerance test (85.2+/-10.0 pmol insulin per mmol glucose) than the control group (136.4+/-23.1 pmol insulin per mmol glucose; P < 0.05) and the IR-group (115.6+/-11.8 pmol insulin per mmol glucose; P = 0.05). Furthermore, the acute insulin response during the first 10 min of an intravenous glucose tolerance test was lower in the IS-group than in the IR-group. Maximal insulin secretion capacity evaluated by C-peptide levels during the hyperglycemic clamp did not differ between the groups. The IR-group had lower rates of whole body glucose uptake (60.1+/-4.6 micromol per lean body mass per minute) than did the control group (84.2+/-5.0 micromol per lean body mass per minute; P < 0.001) or the IS-group (82.6+/-5.9 micromol per lean body mass per minute; P < 0.01) and this was due to reduced glucose nonoxidation. To conclude, both impaired insulin secretion and insulin action seem to be inherited and could represent the primary defects in glucose metabolism in the offspring of NIDDM probands.

Prevalencia de diabetes mellitus no insulinodependiente en la población rural de Durango, México

This study was carried out to determine the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) in rural inhabitants of Durango, Mexico, and some of the risk factors for the disease. A random samples of 30,996 individuals aged 30 years and over was selected from 627 rural communities in Durango. These persons were interviewed between November 1993 and December 1994 to obtain information on several sociodemographic variables. A capillary blood sample was collected from each individual to determine his or her glucose level after 10-12 hours of fasting. Measures of central tendency and dispersion were calculated, and percentage distributions for the study variables were determined. Comparisons among proportions were made utilizing the chi-square test, and means were compared using Student's t test. The strength of associations was estimated with odds ratios, and 95% confidence intervals (CI 95%) were calculated for proportions. The final sample consisted of 31,028 persons, of whom 22,890 (73.8%) were women and 8,138 (26.2%) were men. A total of 1,004 cases of NIDDM were detected (3.2%; CI 95%:3.0 to 3.4), 767 in women and 237 in men. Only 9.2% of the study population was obese. The highest frequency of NIDDM was documented in persons 60 to 69 years of age. Family history of NIDDM was identified in 59.5% of the persons with the disease (CI 95%: 58.9 to 60.0) and in 26.3% of the healthy persons (CI 95%: 25.8 to 26.8). The low prevalence of NIDDM found in this study may be related to the low level of obesity in the population surveyed.

Increased circulating leptin concentrations in insulin-resistant first-degree relatives of patients with non-insulin-dependent diabetes mellitus: relationship to body composition and insulin sensitivity but not to family history of non-insulin-dependent diabetes mellitus.

To explore a possible association between serum concentration of leptin, insulin sensitivity and non-insulin-dependent diabetes mellitus (NIDDM). Forty first-degree relatives of NIDDM patients and 35 control subjects matched for age, gender and body mass index underwent a hyperinsulinaemic (insulin infusion rate 0.6 mU/kg per min) euglycaemic clamp combined with indirect calorimetry. Serum leptin was measured in fasting blood samples obtained before the clamp. All subjects had a normal oral glucose tolerance test. Insulin-stimulated glucose uptake (M) was decreased in the relatives compared with the control subjects (4.58 +/- 0.27 versus 6.06 +/- 0.25 mg/kg per min, P < 0.001). Conversely, serum leptin was increased in the relatives (9.6 x/divided by 1.1 versus 6.1 x/divided by 1.2 ng/ml (geometric mean x/divided by antilog S.E.M.), P < 0.05). A positive correlation was observed between circulating levels of leptin and percentage body fat (P < 0.001) and inverse correlations were found between leptin, M (P < 0.01), maximal aerobic capacity (VO2 max) (P < 0.01), and energy expenditure (P < or = 0.01) in both groups. In multiple linear regression analysis, percentage body fat, gender and M significantly determined the level of leptin (r2 = 0.71, P < 0.001) whereas family history of NIDDM and VO2 max did not. Serum leptin is increased in insulin-resistant offspring of NIDDM patients. The association between leptin, anthropometric measures and insulin sensitivity is, however, comparable with that of a control group. The increased concentrations of serum leptin in the relatives appear to be associated with the insulin resistance, but not with a family history of NIDDM.

Perceived Threat of Illness and Health Protective Behaviors in Offspring of Adults With Non-Insulin-Dependent Diabetes Mellitus

Self-reported measures of perceived threat of illness, health protective behaviors, psychological well-being, and family modeling of health behaviors of 30 adults with a parental history of non-insulin-dependent diabetes mellitus (NIDDM) were compared with responses from 29 adults with a parental history of hypertension and 30 adults with no parental history of chronic illness. The NIDDM risk group reported significantly more perceived threats of NIDDM and hypertension and more weight-control efforts than the controls did. Reports of the NIDDM risk respondents concerning physician screening, healthy diet, and exercise did not differ from reports of individuals without a family history of NIDDM. Perceived threat, psychological well-being, and family modeling did not correlate with health-protective behaviors. The findings suggest that offspring of adults diagnosed with NIDDM perceive themselves to be at risk of NIDDM and engage in health behaviors, such as weight control, to protect themselves from NIDDM onset.

Family history of coronary heart disease is a stronger predictor of coronary heart disease morbidity and mortality than family history of non-insulin dependent diabetes mellitus

The aim of this study was to compare the effect of family history of non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD) as risk factors for CHD morbidity and mortality. Altogether, 394 siblings of NIDDM probands and non-diabetic probands, with and without CHD, were followed for 8 years with respect to CHD events in a prospective population-based study. The baseline study was conducted from 1983 to 1985. Age- and sex-adjusted cumulative occurrence of CHD events was higher in the siblings of the probands with CHD and with NIDDM (13.1%; P = 0.037) and in the siblings of the probands with CHD and without NIDDM (15.4%; P = 0.054), compared with the siblings of the probands without NIDDM and without CHD (4.8%). The incidence of fatal CHD events tended to be higher in a group with a family history of NIDDM and CHD, but the trend was not statistically significant. In univariate logistic regression analyses, a family history of CHD was positively associated with cumulative occurrence of CHD events (odds ratio 2.53, P = 0.009), whereas a family history of NIDDM had no significant association (odds ratio 1.39, P = 0.312). After adjustment for age, sex, family history of NIDDM and major cardiovascular risk factors, the association between family history of CHD and cumulative occurrence of CHD events remained significant (odds ratio 2.25, P = 0.048). In conclusion, the present study indicates that a family history of CHD is a stronger predictor of future CHD events than a family history of NIDDM.

Polymorphism of the glycogen synthase gene in hypertensive and normotensive subjects.

Hypertension and non-insulin-dependent diabetes mellitus (NIDDM) are characterized by a strong genetic component and impaired ability to store glucose as glycogen in skeletal muscle. Impaired insulin activation and altered genetic control of muscle glycogen synthase, the rate-limiting enzyme for glucose storage in skeletal muscle, could provide an explanation for this insulin resistance. We examined whether there is an association between the glycogen synthase gene (Xba I polymorphism) and hypertension in 304 nondiabetic subjects. We examined glucose tolerance with an oral glucose tolerance test and glucose storage in skeletal muscle with the euglycemic insulin clamp technique in combination with indirect calorimetry. The Xba I A2 allele of the glycogen synthase gene was enriched in subjects with hypertension and a family history of NIDDM (48%) compared with normotensive subjects without a family history of NIDDM (6%, P < .0001). The presence of the A2 versus the A1 allele was associated with decreased rates of insulin-stimulated glucose storage in hypertensive subjects (11.2 +/- 2.3 versus 16.9 +/- 2.6 mumol/kg lean body mass per minute, P = .029) but not in normotensive subjects (28.0 +/- 4.6 versus 29.6 +/- 3.7 mumol/kg lean body mass per minute). In conclusion, Xba I polymorphism of the glycogen synthase gene identifies a subgroup of hypertensive subjects with a family history of NIDDM. The data suggest that a locus in the glycogen synthase gene region on chromosome 19 may serve as a "thrifty gene," increasing susceptibility for insulin resistance when exposed to other environmental or genetic factors.

Physical inactivity and glucose intolerance in the multiethnic island of Mauritius

The island nation of Mauritius, located in the southwest Indian Ocean, has a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM) among all of its ethnic groups (Hindu and Muslim Indians, African-origin Creoles, and Chinese). These high rates of NIDDM among groups of varying genetic background provide strong support for the importance of environmental components in the etiology of the disease. Research in Mauritius using a simple activity scale has suggested that physical inactivity may be one of these components. The current investigation further examined the association between glucose tolerance and physical activity in middle-aged nondiabetic residents of Mauritius using a more extensive physical activity questionnaire (the Modifiable Activity Questionnaire). Excluding individuals with NIDDM, a statistically significant (P < 0.05) inverse relationship between physical activity and 2-h post-load glucose concentration was found for both males (rho = -0.14) and females (rho = -0.11). Stratifying by ethnic group, similar inverse correlations were observed in Hindu, Creole, and Chinese males, and in Hindu females (P < 0.05), as well as weaker relationships in Muslim males and Creole females (P < 0.10). Total physical activity remained an independent predictor of 2-h post-load glucose concentration after controlling for body mass index, waist-hip ratio, age, and family history of NIDDM. These data are supportive of a potentially important role of physical activity in the prevention of NIDDM in middle-aged inhabitants of Mauritius.

Metabolic defects in persistent impaired glucose tolerance are related to the family history of non—insulin-dependent diabetes mellitus

Recent studies have suggested that the family history of non—insulin-dependent diabetes mellitus (NIDDM) influences glucose metabolism in subjects with normal glucose tolerance (NGT). However, it is not known whether the family history of NIDDM influences glucose metabolism in impaired glucose tolerance (IGT). We studied in a well-characterized group the impact of family history of NIDDM (diabetes mellitus [DM]-positive) in subjects with IGT on glucose disposal rate (GDR) measured by the euglycemic hyperinsulinemic clamp technique combined with indirect calorimetry. We recruited subjects from our previous population-based studies, and verified their glucose tolerance status twice during the follow-up period of I year. Subjects with NGT (n = 10) and IGT (n = 18) were comparable with respect to age, sex distribution, body mass index, smoking habits, and hypertension. As a group, IGT subjects showed lower GDR than the NGT group (28.6 ± 12.1 v 38.9 ± 13.6 μmol/ kg/ min, P < .05). IGT DM-positive subjects showed a 40% lower GDR than the NGT group ( P < .05) and a 29% lower GDR than IGT DM-negative subjects ( P = NS). IGT DM-positive subjects had lower glucose oxidation ( P = NS, P < .01), glucose nonoxidation ( P = NS, P = .01), and suppression of lipid oxidation ( P = NS, P < .05) during the hyperinsulinemic euglycemic clamp as compared with IGT DM-negative and NGT groups, respectively. In conclusion, in subjects with persistent IGT, the family history of NIDDM is associated with the reduced total whole-body, oxidative, and nonoxidative GDR.

Proinsulin immunoreactivity in identical twins discordant for noninsulin-dependent diabetes mellitus.

Disproportionate elevation [increased proinsulin/insulin (PI/INS) ratio] of PI immunoreactivity is associated with noninsulin-dependent diabetes mellitus (NIDDM). The nature of this abnormality is not known. To address the question of whether genetic factors contribute to hyperproinsulinemia, we measured fasting levels of PI immunoreactivity, intact INS, and C peptide (CP) in 12 pairs of monozygotic twins discordant for NIDDM for a mean (+/- SEM) period of 9 +/- 3 yr. Thirteen age- and body mass index-matched healthy subjects without any family history of NIDDM acted as controls. The nondiabetic twins had levels of fasting INS, CP, PI, PI/CP, and PI/INS similar to those of control subjects. Fasting levels of PI, and PI/CP and PI/INS ratios were significantly 2- to 3-fold elevated in NIDDM twins compared to those in both nondiabetic twins and control subjects. To investigate whether hyperproinsulinemia in these NIDDM patients was due to a differential elevation of intact PI or conversion intermediates, we analyzed PI profiles in NIDDM twins and normal subjects by high pressure liquid chromatography. PI was heterogeneous and consisted mainly of des(31,32)-PI and intact PI in both NIDDM patients and normal subjects, with no major difference in composition between the groups. Small amounts of des(64,65)-PI (0-11%) were measured in some patients and normal subjects. The results suggest that hyperproinsulinemia is not a genetically determined trait per se in NIDDM. Disproportionately elevated PI levels seem to be related to the actual disease process. Further conversion of intact PI and des(31,32)-PI may be equally impaired in NIDDM.

Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.

The increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM) among women with polycystic ovary syndrome (PCOS) has been ascribed to the insulin resistance characteristic of PCOS. This study was undertaken to determine the role of defects in insulin secretion as well as familial factors to the predisposition to NIDDM seen in PCOS. We studied three groups of women: PCOS with a family history of NIDDM (PCOS FHx POS; n = 11), PCOS without a family history of NIDDM (PCOS FHx NEG; n = 13), and women without PCOS who have a family history of NIDDM (NON-PCOS FHx POS; n = 8). Beta cell function was evaluated during a frequently sampled intravenous glucose tolerance test, by a low dose graded glucose infusion, and by the ability of the beta cell to be entrained by an oscillatory glucose infusion. PCOS FHx POS women were significantly less likely to demonstrate appropriate beta cell compensation for the degree of insulin resistance. The ability of the beta cell to entrain, as judged by the spectral power for insulin secretion rate, was significantly reduced in PCOS FHx POS subjects. In conclusion, a history of NIDDM in a first-degree relative appears to define a subset of PCOS subjects with a greater prevalence of insulin secretory defects. The risk of developing NIDDM imparted by insulin resistance in PCOS may be enhanced by these defects in insulin secretion.

Association of the prohormone convertase 2 gene (PCSK2) on chromosome 20 with NIDDM in Japanese subjects.

Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3. PC2 is a type II proinsulin-processing enzyme, and it cleaves the proinsulin molecule on the COOH-terminal side of dibasic peptide, Lys64-Arg65, which joins the C-peptide and the A-chain domains. We have previously cloned and characterized the exon-intron organization of the human PC2 gene (gene symbol PCSK2), localized this gene to human chromosome 20 band p11.2 by fluorescence in situ hybridization, and identified a simple tandem-repeat DNA polymorphism (STRP) in intron 2 of the form (CA)n, suitable for genetic studies. Since non-insulin-dependent diabetes mellitus (NIDDM) is associated with increased secretion of proinsulin and proinsulin-like molecules, we conducted a case-control study to determine whether a genetic variation in PCSK2 might contribute to the development of NIDDM. The study population consisted of 152 Japanese NIDDM subjects and 102 normal healthy nondiabetic control subjects matched for age and body mass index. The subjects were genotyped at the STRP in intron 2, and the results indicated a significant difference (P = 0.004) in the overall allele frequency distribution between the two groups. The A1 allele was found more frequently in NIDDM than in nondiabetic subjects (11 vs. 4%, P = 0.0068). The NIDDM patients were divided into two subgroups according to the presence or absence of the A1 allele.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased Basal Glucose Production and Utilization in Nondiabetic First-Degree Relatives of Patients With NIDDM

To characterize the abnormalities in basal glucose homeostasis in people who are at increased risk for non-insulin-dependent diabetes mellitus (NIDDM), we measured the rates of basal hepatic glucose output (HGO), glucose disappearance, and metabolic clearance of glucose (MCR) in 27 nondiabetic first-degree relatives of NIDDM patients and 16 age-, sex-, and weight-matched healthy control subjects with no family history of NIDDM. Mean fasting plasma glucose was significantly lower (P less than 0.05) in control subjects (mean +/- SE 77 +/- 2 mg/dl) than in relatives (84 +/- 2 mg/dl). Mean basal insulin levels were not significantly different between relatives and control subjects (10.0 +/- 1.5 vs. 7.7 +/- 1.0 microU/ml). Mean basal HGO was significantly lower in control subjects compared with relatives (1.83 +/- 0.07 vs. 2.20 +/- 0.10 mg.kg-1.min-1, P less than 0.05). Mean MCR was similar in relatives (2.58 +/- 0.12 mg.kg-1.min-1) and control subjects (2.35 +/- 0.09 mg.kg-1.min-1). In summary, this study demonstrates that basal hepatic glucose production and glucose utilization are increased in glucose-tolerant first-degree relatives compared with healthy control subjects. We conclude that impaired basal hepatic glucose regulation rather than glucose disposal is present as an early defect in glucose-tolerant first-degree relatives of NIDDM patients.

Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus.

To identify early metabolic abnormalities in non-insulin-dependent diabetes mellitus (NIDDM), we measured sensitivity to insulin and insulin secretion in 26 first-degree relatives of patients with NIDDM and compared these subjects both with 14 healthy control subjects with no family history of NIDDM and with 19 patients with NIDDM. The euglycemic insulin-clamp technique, indirect calorimetry, and infusion of [3-3H]glucose were used to assess insulin sensitivity. Total-body glucose metabolism was impaired in the first-degree relatives as compared with the controls (P less than 0.01). The defect in glucose metabolism was almost completely accounted for by a defect in nonoxidative glucose metabolism (primarily the storage of glucose as glycogen). The relatives with normal rates of metabolism (mean +/- SEM, 1.81 +/- 0.27 mg per kilogram of body weight per minute) and impaired rates (1.40 +/- 0.22 mg per kilogram per minute) in oral glucose-tolerance tests had the same degree of impairment in glucose storage as compared with healthy control subjects (3.76 +/- 0.55 mg per kilogram per minute; P less than 0.01 for both comparisons). During hyperglycemic clamping, first-phase insulin secretion was lacking in patients with NIDDM (P less than 0.01) and severely impaired in their relatives with impaired glucose tolerance (P less than 0.05) as compared with control subjects; insulin secretion was normal in the relatives with normal glucose tolerance. We conclude that impaired glucose metabolism is common in the first-degree relatives of patients with NIDDM, despite their normal results on oral glucose-tolerance tests. Both insulin resistance and impaired insulin secretion are necessary for the development of impaired glucose tolerance in these subjects.