Arginase inhibition improves endothelial function in patients with type 2 diabetes mellitus despite intensive glucose-lowering therapy.

BACKGROUND: Arginase is implicated in the pathogenesis behind endothelial dysfunction in type 2 diabetes mellitus (T2DM) by its inhibition of nitric oxide formation. Strict glycaemic control is not sufficient to improve endothelial function or cardiovascular outcomes in patients with T2DM, thus other treatment strategies are needed. We hypothesized that arginase inhibition improves endothelial function beyond glucose-lowering therapy following glucose optimization in patients with poorly controlled T2DM. METHODS AND RESULTS: Endothelial function was evaluated in 16 patients with poorly controlled T2DM (visit 1) and 16 age-matched controls using venous occlusion plethysmography. T2DM patients were re-evaluated (visit 2) after intensive glucose-lowering regimen. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatations were evaluated before and after 120 min intra-arterial infusion of the arginase inhibitor N(ω)-hydroxy-nor-L-arginine (nor-NOHA). HbA1c was reduced from 87 ± 17 (visit 1) to 65 ± 11 mmol mol-1 (visit 2, P < 0.001). Basal EDV, but not EIDV, was significantly lower in patients with T2DM than in healthy subjects (P < 0.05). EDV and EIDV were unaffected by glucose-lowering regimen in patients with T2DM. Arginase inhibition enhanced EDV in T2DM patients both at visit 1 and visit 2 (P < 0.01). There was no difference in improvement in EDV between the two occasions. EIDV was unaltered by nor-NOHA in T2DM at visit 1, but was slightly improved at visit 2. CONCLUSIONS: Arginase inhibition improves endothelial function in patients with poorly controlled T2DM, which is maintained following glucose optimization. Thus, arginase inhibition is a promising therapeutic target beyond glucose lowering for improving endothelial function in T2DM patients.

Frequency of cancer events with saxagliptin in the SAVOR-TIMI 53 trial.

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial randomized trial of 16,492 patients (placebo, n = 8212; saxagliptin, n = 8280) treated and followed for a median of 2.1 years afforded an opportunity to explore whether there was any association with cancer reported as a serious adverse event. At least one cancer event was reported by 688 patients (4.1%): 362 (4.3%) and 326 (3.8%) in the placebo and saxagliptin arms, respectively (p = 0.13). There were 59 (0.6%) deaths adjudicated as malignancy deaths with placebo and 53 (0.6%) with saxagliptin. Stratification by gender, age, race and ethnicity, diabetes duration, baseline glycated haemoglobin and pharmacotherapy did not show any clinically meaningful differences between the two study arms. The overall number of cancer events and malignancy-associated mortality rates were generally balanced between the placebo and saxagliptin groups, suggesting a null relationship with saxagliptin use over the median follow-up of 2.1 years. Multivariable modelling showed that male gender, dyslipidaemia and current smoking were independent predictors of cancer. These randomized data with adequate numbers of cancer cases are reassuring but limited, by the short follow-up in a trial not designed to test this hypothesis.

Factors determining normalization of glucose intolerance in middle-aged Swedish men and women: a 8-10-year follow-up.

AIMS: To examine factors in middle-aged Swedish men and women predicting the conversion from a state of abnormal glucose regulation to normal glucose tolerance (NGT) after 8-10 years. METHODS: At baseline 3128 men and 4821 women, aged 35-56 years, without previously diagnosed diabetes underwent an oral glucose tolerance test and completed a questionnaire. At follow-up, 2383 men and 3329 women were re-examined. The study group consisted of 156 men and 124 women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both at baseline. RESULTS: The rate of reversal to NGT from IFG or IGT was similar regardless of gender. In participants having IFG or IGT, reversal to NGT was predicted by low fasting and 2-h insulin, homeostasis model assessment of insulin resistance and of pancreatic beta cell function, body mass index and waist circumference without differences between gender and baseline glucose tolerance group. Low 2-h glucose, however, predicted reversal to NGT in men with IFG at baseline, but not in men with IGT at baseline, or in women with either IFG or IGT at baseline. Men reverting to NGT had higher coffee consumption and women had higher baseline leisure-time physical activity. In multiple logistic regression, including all participants, low fasting and 2-h glucose remained independent predictors of reverting to NGT. CONCLUSIONS: Factors predicting reversal to NGT were measures correlated with low insulin resistance, but also lower insulin secretion, perhaps indicating a lower pancreatic beta cell workload in those who reverted. In men, but not in women, low 2-h glucose was of predictive value.

Effects of insulin vs. glibenclamide in recently diagnosed patients with type 2 diabetes: a 4-year follow-up.

AIM: To compare effects of early insulin vs. glibenclamide treatment on beta-cell function, metabolic control and quality of life (QL) in recently diagnosed patients with type 2 diabetes. METHODS: Forty-nine patients with type 2 diabetes diagnosed 0-2 years before inclusion were randomized to two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide at six diabetic clinics in Sweden. C-peptide-glucagon tests were performed yearly after 3 days of withdrawal of treatment. RESULTS: Thirty-four patients completed 4 years of study. Daily dose of insulin was increased from 20.4 +/- 1.8 U at year 1 to 26.1 +/- 2.9 U at year 4 (p = 0.005). Glibenclamide dosage increased from 2.7 +/- 0.4 mg at year 1 to 4.5 +/- 0.8 mg at year 4 (p = 0.02). Weight increased more in insulin than in glibenclamide treated (+4.4 +/- 0.8 vs. +0.3 +/- 1.0 kg, p < 0.005). Following short-term withdrawal of treatment, the C-peptide responses to glucagon were significantly higher in the insulin vs. glibenclamide group at years 1 (p < 0.01) and 2 (p < 0.02). HbA1c improved identical during the first year but thereafter deteriorated in the glibenclamide group (p < 0.005 for difference at year 4). Ratios of proinsulin to insulin were higher during treatment in glibenclamide- vs. insulin-treated patients after year 2. QL after 4 years as measured by the MOS 36-item Short-Form Health Survey (SF-36) form was not significantly altered. CONCLUSIONS: In a 4-year perspective, beta-cell function deteriorated in both groups. However, deterioration occurred faster in the glibenclamide group, indicating that alleviating demands on secretion by insulin treatment is beneficial.

Glucose potentiation of arginine-induced insulin secretion is impaired in subjects with a glucokinase Glu256Lys mutation.

Insulin and glucagon release and insulin sensitivity were investigated in patients with glucokinase deficiency. Five subjects with a missense mutation (Glu256Lys) were studied. They were compared with six healthy subjects with low insulin response but normal glucose tolerance. Insulin and glucagon levels were measured at blood glucose 7.1 +/- 0.1 mmol/l and at 10.9 +/- 0.2 mmol/l with or without arginine (5 g i.v.). Insulin sensitivity was assessed as the ratio between infused glucose and the insulin level (M:I) during hyperglycemic clamps. Glu256Lys subjects were nonobese and had fasting blood glucose 6.7 +/- 0.1 mmol/l (P < 0.001 vs. control group). Insulin release was reduced in response to 11 mmol/l glucose (61% of control group, P < 0.05) as well as to arginine in the presence of 11 mmol/l glucose (54% of control group, P < 0.01). Also, the slope of potentiation, i.e., the enhancement of arginine-induced release as a function of prevailing glucose concentration, was reduced (delta insulin/delta glucose, 47% of control group, P < 0.05). As for glucagon release, the response to arginine was not inhibited normally by glucose, resulting in threefold higher levels at 11 mmol/l glucose versus control subjects. Insulin sensitivity, assessed as M:I, was significantly (P < 0.05) reduced (55% of control group). Glucokinase deficiency thus affects not only insulin responses to glucose per se but also glucose potentiation of responses to non-nutrient secretagogues. Abnormalities in glucagon release and insulin sensitivity coexist with attenuated insulin responses in glucokinase-deficient subjects.

Low birth weight, family history of diabetes, and glucose intolerance in Swedish middle-aged men.

OBJECTIVE: To investigate the association between low birth weight and glucose intolerance in relation to family history of diabetes. RESEARCH DESIGN AND METHODS: We conducted a population-based cross-sectional study of 2,237 men born in 1938-1957 in four municipalities in the outskirts of Stockholm, 50% of whom had a family history of diabetes (at least one first-degree or two second-degree relatives with diabetes). Oral glucose tolerance testing detected 35 cases of type 2 diabetes, 102 cases of impaired glucose tolerance, and 57 cases of impaired fasting glucose. RESULTS: In subjects without a family history of diabetes, low (< or = 3,000 g) birth weight was associated with an odds ratio of 2.3 (95% confidence intervals = 0.4-14.4) for diabetes, 1.8 (0.7-4.3) for impaired glucose tolerance, and 3.3 (1.0-10.4) for impaired fasting glucose. In subjects with a family history of diabetes, the corresponding figures were approximately similar, except for diabetes, for which the odds ratio was 5.4 (2.0-14.9). For men with low birth weight in combination with a family history of diabetes, the odds ratio was 10.9 (2.9-41.2) for diabetes, 2.4 (1.1-5.6) for impaired glucose tolerance, and 5.9 (2.1-16.3) for impaired fasting glucose. CONCLUSIONS: This study indicated that low birth weight is associated with type 2 diabetes, impaired glucose tolerance, and impaired fasting glucose in men. This finding was most pronounced in subjects with diabetes in the family, but it was also indicated in those without a family history of diabetes. Men with the combination of low birth weight and family history of diabetes seem to be at particularly high risk of developing type 2 diabetes.

Relationship between insulin responses to D-glucose and to L-arginine in women with a history of gestational diabetes.

The relationship between insulin responses to glucose and to arginine was studied in non-obese women with previous gestational diabetes (PGD). One group, n = 10, had normal glucose tolerance (NGT) by WHO criteria and another, n = 8, had impaired glucose tolerance (IGT). A third group of women without PGD, n = 12, was also studied. A hyperglycaemic clamp (blood glucose level 11 mM) and an arginine stimulation test (150 mg/kg L-arginine followed by 10 mg/kg.min) were performed on separate days. The ratios of arginine to glucose responses 0-10 min differed: they were 1.00 for non-PGD, 1.29 for NGT and 1.46 for IGT (P < 0.02 vs non-PGD). A further difference between groups was the ratio between first- and second-phase glucose-induced insulin secretion, which was significantly decreased in IGT, 0.72, compared with NGT, 0.98 (P < 0.01), and non-PGD, 1.05 (P < 0.005). However, within each group insulin responses 0-10 min to glucose and arginine were strongly correlated: for NGT (r = 0.75, P < 0.05), for IGT (r = 0.85, P < 0.01) and for women without PGD (r = 0.69, P < 0.05). Insulin sensitivity, as assessed by the M/I ratio, was non-significantly decreased in IGT (0.18 +/- 0.03 mg/kg.min per mU/l vs 0.26 +/- 0.03 in NGT and 0.28 +/- 0.03 in non-PGD, P < 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

[Intake of disopyramide led to diagnosis of insulinoma]. / Intag av disopyramid ledde till insulinomdiagnos.

A single dose of 250 mg disopyramide provoked severe hypoglycaemia and confusion in a 75-year-old woman. During subsequent investigation, fasting provoked symptomatic hypoglycaemia (venous blood glucose, 1.6 mumol/1) after 23 hours, plasma concentrations of insulin and C peptide then being 19 micrograms/ml and 0.85 pmol/l, respectively; computerised tomography and ultrasonography of the pancreas n.a.d. However, at laparotomy, a 10 mm diameter insulinoma was detected by intra-operative ultrasonography and palpation. The tumour was removed. To our knowledge, this is the first reported case of an insulinoma being detected due to intake of disopyramide.

Pathophysiology and treatment of patients with type 2 diabetes exhibiting failure to oral drugs.

It is generally accepted that a poor glycaemic control increases the risk for development of vascular complications in diabetic patients. This advocates for early introduction of insulin treatment in patients with type 2 diabetes exhibiting a secondary failure to oral treatment. This strategy is facilitated by introduction of long-acting insulin glargine and biphasic insulin aspart 70/30. The introduction of Glucagon-like peptide-1 (GLP-1) mimetics and dipeptidyl peptidase 4 (DPP-4) inhibitors in treatment of type 2 diabetes will however, to a large extent, influence therapeutic policy. Thus we suggest that DPP-4 inhibitors or long-acting GLP-1 mimetics will be used as either first-line therapy or as an early addition to metformin. The already generated results in animal and clinical studies suggest that these two classes of antidiabetic drugs may in addition to improving glycaemic control protect islet beta-cell mass and thereby postpone development of a secondary failure. When patients treated with metformin, sulfonylurea (SU), tiazolidinediones or a combination of these drugs fail, the GLP-1 mimectics may be preferred to insulin treatment. First, the risk of hypoglycaemia is less if not combined with SU. Secondly, the body weight is usually decreased while insulin treatment increases weight. Patients not responding to GLP-1 mimetics or experiencing significant side effects will be treated with insulin. Irrespective of the policy used for the drug treatment of type 2 diabetes, exercise and proper diet will remain important for optimization of metabolic control.

K-value and low insulin secretion in a non-obese white population: predicted glucose tolerance after 25 years.

AIMS/HYPOTHESIS: Insulin resistance and insulin deficiency are proposed as risk factors for IGT and type 2 diabetes. We assessed the predictive value of initial parameters for the outcome of an OGTT performed 24.3+/-2.9 years later in an unselected healthy non-obese population. METHODS: The K-value of an IVGTT was determined in 267 healthy subjects (mean+/-SD: age 31.0+/-12.0 years, BMI 21.8+/-2.8 kg/m(2)). First-phase insulin response to a glucose infusion test was estimated as an incremental 5- or 10-min (DeltaI5 or DeltaI10) value, and as insulinogenic indices (DeltaI5/DeltaG5 or DeltaI10/DeltaG10) adjusted for insulin sensitivity determined by homeostasis model assessment for insulin resistance ([DeltaI5/DeltaG5]/HOMA-IR). RESULTS: At follow-up, six subjects had type 2 diabetes and 47 had IGT; 214 retained normal glucose tolerance. Insulin sensitivity and early (30 min) insulin response decreased with decreasing outcome OGTT. Blood glucose (2 h) at OGTT correlated positively with initial age and BMI, and negatively with DeltaI5/DeltaG5, (DeltaI5/DeltaG5)/HOMA-IR and K-value. In multiple linear regression analysis, (DeltaI5/DeltaG5)/HOMA-IR, DeltaI10, K-value, age, HOMA estimate of insulin secretion, and fasting plasma glucose were significantly associated with 2-h OGTT blood glucose. Similar results were obtained on comparing differences between subjects with normal and decreased (IGT+diabetes) glucose tolerance. CONCLUSIONS/INTERPRETATION: In 267 non-obese healthy subjects, initial K-value and first-phase insulin response to glucose adjusted for insulin sensitivity, but not insulin sensitivity itself, were strong predictors of the outcome of an OGTT performed 25 years later. Thus, in contrast to obese or other high-risk populations, in lean subjects, decreased beta cell function, but not insulin resistance itself, determines future glucose tolerance.

Impact of nicotinic acid treatment on insulin secretion and insulin sensitivity in low and high insulin responders.

The aim of the study was to evaluate the effect of nicotinic acid (NA) on glucose tolerance, insulin secretion and sensitivity in relation to perturbations of non-esterified fatty acids (NEFA) and previously characterized insulin responses. Healthy subjects (n = 12) were treated for 14 days with incremental doses of NA reaching 2 g day-1. Before NA and on day 14 a hyperglycaemic clamp (11 mmol l-1) was performed with arginine (5 g i.v.) stimulation before and during the clamp. Fasting serum levels of NEFA were evanescently decreased on day 3 (-38%; p < 0.01) and day 7 (-33%; p < 0.05), but not on day 14 (-14%; NS). NA treatment did not significantly affect levels of fasting blood glucose, insulin, C-peptide, proinsulin or glucagon. NA treatment lowered the amount of infused glucose necessary to achieve clamp levels 48 (8) vs. 61 (10) mumol kg-1 min-1 (p < 0.01). Incremental increases in fasting NEFA levels correlated (r = -0.72) with decreased insulin sensitivity as reflected by M/I ratios (the amount of glucose infused, minus glucosuria, divided by the mean insulin level) (p < 0.01). Insulin and glucagon responses to arginine and glucose were similar before and after NA in subgroups with initially low and high insulin responses to glucose. NA-induced insulin resistance in this study is (a) less than previously reported; (b) not associated with changes in insulin secretory responsiveness, but is (c) influenced by an individually variable NA effect on fasting NEFA levels. Our results do not indicate that NA treatment can be used to test the capacity of B cells to cope with insulin resistance.

Characteristics of insulin release in healthy subjects and in subjects with a glucokinase (Glu 256 Lys) Mutation.

Healthy subjects with previously observed low insulin responses to i.v. glucose have been further characterized. A low insulin response was relatively stable over decades. Adaptability to increased demands for insulin secretion was poor. Hence, dexamethasone treatment for 60 h induced insulin resistance but did not enhance insulin responses to glucose or to arginine. Birth weight was not associated with low insulin responses. Data are compatible with major influences of inherent factors on insulin secretion. Low insulin responses in healthy subjects were compared with responses in glucokinase-deficient subjects. Second phase of glucose-induced insulin secretion and glucose-dependent potentiation of arginine-induced secretion were decreased in both groups. However, the first phase response to glucose was higher in glucokinase-deficient subjects. Hence, decreased first phase insulin secretion is not specifically linked to deficiencies in beta-cell metabolism.

Dexamethasone treatment fails to increase arginine-induced insulin release in healthy subjects with low insulin response.

We have compared insulin responses to L-arginine before and during dexamethasone treatment in healthy subjects, previously classified as subjects with either high or low insulin response according to a standardized glucose infusion test. Arginine stimulation was administered as a 150 mg/kg bolus followed by 10 mg.kg-1.min-1 to six subjects with high insulin response and to seven subjects with low insulin response. Before dexamethasone treatment the incremental insulin level during 0-10 min of arginine was higher in subjects with high (36.5 +/- 6.8 microU/ml) than in subjects with low response (14.5 +/- 2.3 microU/ml), p less than 0.01 for difference. Dexamethasone treatment (6 mg/day for 60 h) markedly enhanced the insulin response to arginine in subjects with high response (+99% 0-30 min) but failed to affect the subjects with low response (+4% 0-30 min). The C-peptide response to arginine exhibited similar differences between groups. Decreased responsiveness to arginine in subjects with low insulin response, especially during dexamethasone treatment, suggests a Beta-cell capacity defect although a decreased potentiating-sensing effect of glucose cannot be completely ruled out.

Effect of long term glycemic control on the onset of retinopathy in iddm subjects. A longitudinal and retrospective study.

A random sample of 78 IDDM patients were studied retrospectively with regard to longitudinal glycemic control from onset of diabetes in relation to onset of retinopathy from 10-20 years of the disease. During the latter period 40 patients developed retinopathy (retinopathy group) whereas 38 did not (no retinopathy group). Sex ratio as well as age at onset of diabetes was similar between the two groups. Also glycemic control was similar during the first five years of diabetes as assessed from glucose determinations in urine and blood. However, during the period from 5-10 years of diabetes duration glycemic control of the retinopathy group deteriorated significantly in comparison to previous years and in comparison with the non-retinopathy group. The frequency of control visits did not differ between groups; however patients in the retinopathy group more frequently changed from one institution of treatment to another than did the other patients. This study demonstrates that glycemic control deteriorates with time in a sub-group of IDDM subjects and supports the concept that onset of retinopathy depends on cumulative exposure to hyperglycemia.

Enhancement of B-cell secretion by blood glucose normalization in type 2 diabetes is associated with fasting C-peptide levels.

OBJECTIVES: To investigate (i) the variability of beneficial effects achieved by short-term near-normalization of blood glucose in type 2 diabetes patients, and (ii) the relationship of beneficial effects to individual characteristics of diabetes. DESIGN: Arginine-induced insulin and glucagon release tested at two glucose levels before and after 3 days of intensive insulin treatment. SETTING: The Department of Endocrinology and Diabetology, Karolinska Hospital, Stockholm, Sweden. SUBJECTS: Type 2 diabetes patients with poor metabolic control sampled from an area-based population of diabetes patients. RESULTS: Levels of fasting blood glucose declined from 15.0 +/- 0.9 to 8.5 +/- 0.7 mmol L-1, C-peptide from 0.81 +/- 0.06 to 0.49 +/- 0.05 nmol L-1 and percent proinsulin (of total IRI) from 7.8 +/- 1.0 to 3.2 +/- 0.6%. At comparable glucose levels arginine-induced insulin secretion was enhanced 46.3 +/- 19.5% (range -36 to 220%). Enhancement correlated with extent of blood glucose normalization and also with fasting C-peptide levels and with overweight. Arginine-induced glucagon secretion was nonsignificantly depressed (17.2 +/- 7.4%, range -59 to 29%). Insulin sensitivity assessed by M:I ratio was increased by a median of 95%. CONCLUSIONS: In type 2 diabetes patients reversibility of the effects of poor metabolic control on B-cell function is variable. Variability is related to B-cell mass in individual patients with type 2 diabetes.

Insulin responses to glucose in healthy males are associated with adult height but not with birth weight.

OBJECTIVE: To investigate the relations between height, birth weight and insulin secretion. SUBJECTS AND DESIGN: Subjects were selected from a register of all male healthy volunteers who had previously participated in insulin secretion studies. All men in whom a 1-h glucose infusion test had been performed on two or more occasions were selected (n = 88). Subjects were divided into two equally sized groups according to 0-10-min insulin responses. MAIN OUTCOME MEASURES: Insulin responses were measured by standardized glucose infusion tests. Heights and weights were measured on these occasions. Birth weights were obtained from questionnaires and validated from obstetric records. RESULTS: The average height for the 50% of subjects with the lowest insulin response was 3.5 cm less [95% confidence interval (CI): 1.1 to 5.9] than in those with the highest response, P < 0.005. These differences were also significant when expressed relative to heights of national cohorts with the same years of birth [1.7% less in those with lowest response (95% CI: 0.3 to 3.0), P < 0.02 for difference]. However, birth weight (known to 69% of subjects) was not associated with insulin response (3706 +/- 126 g in the 50% with lower insulin response, 3590 +/- 136 g in those with higher insulin response). CONCLUSIONS: An early insulin response to glucose associates with postnatal growth. This suggests that physiological variations in postnatal insulin secretion can influence growth and height in healthy subjects. Furthermore, in the present study group, a low birth weight is not an important determinant of postnatal insulin secretion.

Long-term stability of low insulin responses to glucose in non-diabetic subjects.

We investigated the stability of the insulin response to glucose in healthy subjects by making retrospective comparisons of insulin responses after two 60 min glucose infusion tests performed many years apart. The subjects (N = 49) were divided into two lower and two higher quartiles as assessed by the incremental 0-10 min insulin area during the initial glucose infusion test. Ages were initially 32.3 +/- 2.8 years in lower quartiles and 26.6 +/- 1.1 in higher quartiles and body mass indexes 21.6 +/- 0.6 kg/m2 and 21.8 +/- 0.5, respectively. The interval between the first and second glucose infusion tests was 8.1 +/- 2.8 years for lower quartiles and 10.4 +/- 1.3 for higher quartiles. In lower quartiles, the 0-10 min insulin area at first testing was 157.1 +/- 15.9 mU/l x 10 min and at follow-up 202.2 +/- 26.6 (+29%, NS). In higher quartiles, the insulin area decreased from 654.8 +/- 70.6 mU/l x 10 min at first testing to 489.8 +/- 53.6 at follow-up (-25%, p less than 0.05). The 0-60 min glucose area did not change significantly between glucose infusion tests in lower quartiles (+5%), but did increase by 12% (p less than 0.005) in higher quartiles. Only one subject of the lowest quartile at first testing changed to higher quartiles at follow-up. Predictable "regression toward the mean" at follow-up was moderate, hence the individual insulin response to glucose was relatively stable with time. This finding is compatible with the hypothesis that genetic factors are of major importance for the insulin response to glucose.

Family history of diabetes in middle-aged Swedish men is a gender unrelated factor which associates with insulinopenia in newly diagnosed diabetic subjects.

We have investigated the association of a family history of diabetes with glucose tolerance in a population of Swedish men. All men 35-54 years of age in 1992 and living in four different local municipalities of the outer Stockholm area were screened by questionnaire. From 10236 completed questionnaires 1622 men, selected for presence of such a history but without known diabetes, as well as 1507 men without a family history underwent an oral glucose tolerance test. Diabetes (2 h-plasma glucose levels > 11.0 mmol/l) was detected in 55 and impaired glucose tolerance (plasma glucose levels 7.8-11.0 mmol/l) in 172 subjects. The odds ratio of diabetes, associated with a family history, was 4.1, confidence interval 2.1-8.3 and for impaired glucose tolerance 1.6, confidence interval 1.2-2.3. Influence of a family history was measurable also within the range of normal 2-h glucose concentrations: compared to 2-h glucose levels < 3.8 mmol/l; the odds ratio associated with a family history was 1.4, confidence interval 1.1-1.7 and 1.3, confidence interval 1.1-1.6 for concentrations 4.8-5.7 mmol/l and 5.8-7.7 mmol/l respectively. The odds ratio of diabetes and impaired glucose tolerance among men with a family history increased with number and closeness of relatives with diabetes but was not affected by the gender of the family member. Overweight (BMI > 25.0 kg/m2) increased the odds ratio of diabetes in subjects with a family history, the odds ratio being 24, confidence interval 3-177, when both conditions were present. In subjects with Type II (non-insulin-dependent) diabetes mellitus discovered during the investigation, the presence of a family history of diabetes was associated with decreased insulin secretion rather than insulin resistance as assessed by fasting insulin, homeostasis model assessment, and the 2-h insulin response to the oral glucose tolerance test. We conclude that a family history of diabetes strongly but independently of gender associates with decreased glucose tolerance. Furthermore, the results are compatible with a major role for low insulin secretion in the diabetogenic influence of a family history of diabetes in middle-aged Swedish men. Lastly, the very high risk for diabetes in middle-aged men with both a family history of diabetes and obesity indicates that such people should, for the purpose of therapeutic intervention, be identified in the general population.

Weight history, glucose intolerance, and insulin levels in middle-aged Swedish men.

The association between weight history and glucose intolerance was examined in a cross-sectional study consisting of 3,128 Swedish men aged 35-56 years, 52 percent of whom had a family background of diabetes mellitus. Oral glucose tolerance testing detected 55 cases of type 2 (non-insulin-dependent) diabetes and 172 cases of impaired glucose tolerance. Among men with no family history of diabetes, the estimated odds ratios for impaired glucose tolerance associated with short (<5 years) and long (> or =10 years) durations of obesity (body mass index (weight (kg)/height2 (m2) > or =25.0) were 1.3 (95% confidence interval (CI) 0.2-7.7) and 11.8 (95% CI 3.3-41.9), respectively. Among men with a family history of diabetes, the odds ratios were 2.0 (95% CI 0.8-4.7) and 4.0 (95% CI 1.8-9.1), respectively. Corresponding estimates of the odds of type 2 diabetes, adjusted for family history of diabetes, were 1.9 (95% CI 0.5-7.1) and 7.3 (95% CI 2.2-23.7), respectively. The odds of high (> or =30.0 mU/liter) fasting insulin levels in subjects with impaired glucose tolerance were 6.9 (95% CI 0.6-74.2) and 21.0 (95% CI 2.1-206.4) for short and long durations of obesity, respectively. Corresponding estimated odds of low 2-hour insulin response (< or =71.9 mU/liter) were 0.7 (95% CI 0.2-2.9) and 3.3 (95% CI 1.2-8.9). Homeostasis model assessment of insulin resistance yielded an odds ratio of 6.7 (95% CI 0.6-73.4) for a short duration of obesity and 20.0 (95% CI 2.0-200.6) for a long duration. Examination of beta-cell function with homeostasis model assessment resulted in odds ratios of 0.2 (95% CI 0.0-1.6) and 2.0 (95% CI 0.7-5.4) for short and long durations of obesity, respectively. These data indicate that obesity decreases glucose tolerance by way of progressively increased insulin resistance and, in the case of prolonged duration, by decreased insulin secretion as well.

Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients.

Using R-beta-[1-(11)C]hydroxybutyrate and positron emission tomography, we studied the effect of acute hyperketonemia (range 0.7-1.7 micromol/ml) on cerebral ketone body utilization in six nondiabetic subjects and six insulin-dependent diabetes mellitus (IDDM) patients with average metabolic control (HbA(1c) = 8.1 +/- 1.7%). An infusion of unlabeled R-beta-hydroxybutyrate was started 1 h before the bolus injection of R-beta-[1-(11)C]hydroxybutyrate. The time course of the radioactivity in the brain was measured during 10 min. For both groups, the utilization rate of ketone bodies was found to increase nearly proportionally with the plasma concentration of ketone bodies (1.0 +/- 0.3 micromol/ml for nondiabetic subjects and 1.3 +/- 0.3 micromol/ml for IDDM patients). No transport of ketone bodies from the brain could be detected. This result, together with a recent study of the tissue concentration of R-beta-hydroxybutyrate in the brain by magnetic resonance spectroscopy, indicate that, also at acute hyperketonemia, the rate-limiting step for ketone body utilization is the transport into the brain. No significant difference in transport and utilization of ketone bodies could be detected between the nondiabetic subjects and the IDDM patients.