Prevalence of insulin deficiency among initially non-insulin-dependent middle-aged diabetic individuals.

The endogenous insulin secretion capacity of 171 insulin-treated middle-aged persons with diabetes (81 men, 90 women) of the Kuopio University Central Hospital district (population 250,000), East Finland, was measured by the C-peptide response to glucagon. The prevalence of insulin deficiency among initially non-insulin-dependent diabetic (NIDDM) individuals was calculated on the basis of those who were initially treated with diet or oral drugs and 3 yr or more after diagnosis had been treated with insulin and were insulin deficient in this study. The prevalence of complete insulin deficiency (postglucagon C-peptide undetectable) was among initially NIDDM individuals of the same region, 0.7% in men and 1.2% in women. Using the postglucagon C-peptide level of 0.20 nmol/L as a cut-off point, the prevalence of insulin deficiency was 2.0% in men and 1.9% in women and, on the basis of C-peptide level of 0.60 nmol/L, the prevalence of insulin deficiency was 3.5% in men and 2.7% in women. Our data suggest that the deterioration of insulin secretion capacity in NIDDM to the level that leads to insulin dependency occurs less often than has been previously suggested.

Hyperinsulinemia cluster predicts the development of type 2 diabetes independently of family history of diabetes.

OBJECTIVE: The aim of this prospective study was to determine risk factor clusters predicting type 2 diabetes in subjects with and without family history of diabetes by applying factor analyses. RESEARCH DESIGN AND METHODS: The study population consisted of 309 siblings of diabetic (DM+) or nondiabetic (DM-) probands. Risk factors, including lipids, lipoproteins, blood pressure, and glucose tolerance status, were measured at the baseline study and 8 years later. RESULTS: Siblings in the DM+ group had a significantly higher risk of diabetes (odds ratio [OR] = 3.25; P = 0.002) than siblings in the DM- group. Altogether, factor analyses revealed four significant factors in both the DM+ and DM- groups (the percentage of cumulative variance explained 62-66%). Of these, factor 1 (percentage of variance, 27-29%) was characterized by high loadings for BMI, hypertension, glucose area, insulin area (the highest loading), and triglycerides in both the DM+ and DM- groups; therefore, factor 1 can be interpreted as a hyperinsulinemia factor. Also, other factors were essentially similar in both groups. Hyperinsulinemia factor was similarly associated with the risk of developing diabetes in the DM+ group (OR = 4.33, 95% CI 2.29-8.19; P < 0.001) and the DM- group (OR = 4.22, 95% CI 2.02-8.81; P < 0.001) in logistic regression analyses. CONCLUSIONS: Our results indicate that a cluster of cardiovascular risk factors around hyperinsulinemia is an important predictor of diabetes in 8-year follow-up independent of family history of diabetes.

Factors associated with fasting and postglucagon plasma C-peptide levels in middle-aged insulin-treated diabetic patients.

We studied fasting and postglucagon plasma C-peptide levels and factors associated with them in two representative studies of middle-aged insulin-treated diabetic patients whose diabetes had been diagnosed after the age of 30 yr. Altogether, 75 men and 79 women from East Finland and 83 men and 62 women from West Finland aged 45-64 yr were studied. Of these patients, 44.4% had undetectable fasting and 38.5% undetectable postglucagon C-peptide concentrations. The phi-coefficient expressing the concordance of fasting and postglucagon C-peptide concentrations in the classification of diabetic patients into nonresponders and responders was .75 in men and .91 in women. In multiple stepwise regression analyses, body mass index (BMI) and the period between diabetes diagnosis and the initiation of insulin treatment were positively and duration of diabetes inversely associated with fasting and postglucagon C-peptide levels in both sexes. We concluded that 1) insulin deficiency is not uncommon in middle-aged insulin-treated diabetic patients whose diabetes has been diagnosed after the age of 30 yr; 2) fasting C-peptide levels contain basically the same information as postglucagon C-peptide levels; and 3) a low BMI, a need for insulin treatment soon after the diagnosis of diabetes, and a long duration of diabetes are predictive of insulin deficiency.

Five-year follow-up study on plasma insulin levels in newly diagnosed NIDDM patients and nondiabetic subjects.

A representative group of middle-aged (45- to 64-yr-old) patients with non-insulin-dependent diabetes mellitus (NIDDM) (n = 133; 70 men, 63 women) were examined at the time of diagnosis and 5 yr afterward for metabolic control and insulin response to oral glucose; 144 nondiabetic control subjects (62 men, 82 women) were similarly examined twice between 5-yr intervals. At the 5-yr examination, 56 of the diabetic patients (36 men, 20 women) were on diet therapy only, 60 (27 men, 33 women) received oral antidiabetic drugs, and 5 were treated with insulin. The metabolic control of diabetic patients was poor at the time of diagnosis and 5-yr examination. Fasting plasma insulin levels were higher in diabetic patients than in control subjects both at baseline (23 +/- 2 vs. 14 +/- 1 mU/L, P less than 0.01, for men; 26 +/- 2 vs. 15 +/- 1 mU/L, NS, for women) and 5-yr examination (19 +/- 1 vs. 16 +/- 2 mU/L, NS, for men; 29 +/- 5 vs. 15 +/- 1 mU/L, P less than 0.05, for women). The frequency of insulin deficiency in diabetic patients based on a postglucagon (1 mg i.v.) C-peptide level less than 0.60 nM was 3.3% at the 5-yr examination, indicating that true insulin deficiency was uncommon during the first years after diagnosis of diabetes in middle-aged subjects.

Lack of effect of hepatic enzyme induction on metabolic control in patients with type 2 (non-insulin-dependent) diabetes.

A placebo-controlled, double-blind crossover study was carried out in 11 non-insulin-dependent (type 2) diabetic patients to find out the effects of a hepatic enzyme inducer (phenobarbital, 100 mg/day for 2 months) on the metabolic control, plasma C-peptide, insulin, serum, and lipoprotein lipid levels. Phenobarbital induced a significant increase in hepatic antipyrine metabolizing activity, but no significant changes were found in fasting or postload blood glucose, plasma C-peptide, or insulin levels during the study. There was a significant increase in serum total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, as well as in serum total and very low-density lipoprotein triglycerides, during phenobarbital treatment as compared with placebo.

Effects of a very-low-calorie diet on metabolic control and cardiovascular risk factors in the treatment of obese non-insulin-dependent diabetics.

Ten obese non-insulin-dependent diabetics (six men, four women) with secondary drug failure were treated with a hypocaloric diet only (2100-3350 kJ/d) for 3 mo to assess the effects of weight reduction on metabolic control, energy production rate, and cardiovascular risk factors. During the 3 mo of follow-up the mean body weight decreased from 101.0 +/- 7.2 (means +/- SEM) to 87.2 +/- 5.5 kg (p less than 0.001). Basal energy production rate (kJ/min) decreased by 8.5%. Fasting blood glucose declined from 12.3 +/- 0.4 to 10.5 +/- 0.7 mmol/L (p less than 0.05) but mean diurnal glucose and glycosylated hemoglobin A1c did not change significantly. Serum total cholesterol was decreased at 2 wk but at 3 mo it did not differ significantly from the baseline value. A marked reduction was observed in serum triglycerides after 3 mo (4.57 +/- 1.0 vs 2.18 +/- 0.26 mmol/L, p = 0.012). The high-density lipoprotein (HDL) cholesterol increased after weight reduction (0.96 +/- 0.06 vs 1.11 +/- 0.05 mmol/L, p = 0.009). A significant decline was found in both systolic (152 +/- 6 vs 133 +/- 3 mm Hg, p = 0.004) and diastolic blood pressure (92 +/- 3 vs 81 +/- 3 mm Hg, p = 0.007). There was no evidence of linoleic acid deficiency after this diet.

Effect of inorganic chromium supplementation on glucose tolerance, insulin response, and serum lipids in noninsulin-dependent diabetics.

A placebo-controlled double-blind cross-over study was carried out to assess the effect of chromium supplementation (200 micrograms trivalent chromium daily for 6 wk) on glucose tolerance, insulin response, long-term diabetic control, and serum lipids in 10 noninsulin-dependent diabetics aged 37 to 68 yr. After chromium supplementation 24-h urinary chromium excretion showed a 9-fold increase indicating a positive chromium balance in the subjects. There was no significant difference between chromium supplementation and placebo periods in glucose tolerance and in fasting or 2-h postglucose serum insulin levels but the 1-h postglucose serum insulin level was slightly lower on chromium supplementation than on the placebo (55 +/- 9.0 versus 64 +/- 11; p less than 0.01, paired t test). Serum total cholesterol and triglycerides and their high-density, low-density, and very low-density lipoprotein subfractions showed no change after chromium supplementation as compared to the placebo period.

Effect of vigabatrin on epilepsy in mentally retarded patients: a 7-month follow-up study.

We studied the antiepileptic potency of vigabatrin (gamma-vinyl GABA, GVG) as an open trial in a group of 36 mentally handicapped patients with drug-resistant epilepsy (30 had seizures of partial onset and 6 had primary generalized [PG] tonic-clonic convulsions). With this treatment, 13 (43%) of the patients with seizures of partial onset and 2 (33%) with PG had more than 50% reduction in seizure frequency. The antiepileptic effect appeared during the first month of therapy and continued throughout the 7-month study. The side effects were mild: tiredness, aggressiveness, and ataxia. Other antiepileptic drugs remained at baseline levels during GVG therapy. GVG did not alter EEG recordings. Our results suggest that GVG is effective for treatment of intractable epilepsy, especially the partial type, in mentally retarded patients. Longer follow-up is needed, however, to determine that the clinical effect is maintained and that no severe side effects appear.

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.

Familial aggregation of non-insulin dependent diabetes and coronary heart disease are accompanied by different effects on serum lipids, lipoproteins and apolipoproteins.

This study was designed to investigate whether the presence of non-insulin-dependent diabetes mellitus (NIDDM) or coronary heart disease (CHD) in probands have different effects on serum lipid, lipoprotein and apolipoprotein concentrations in the first-degree relatives. Altogether 161 probands (114 men, 47 women) and 788 first-degree relatives of these probands (174 brothers, 246 sisters, 180 sons, 188 daughters) were included in the analyses. The presence of NIDDM in the proband was associated with lowered total, LDL and HDL cholesterol and apolipoprotein A1 and elevated total triglyceride levels in the brothers (P less than 0.05) and elevated total and LDL cholesterol levels in the sisters (P less than 0.05). Total LDL and VLDL cholesterol and apolipoprotein B were higher (P less than 0.05) and HDL/total cholesterol ratio and apolipoprotein A1/B ratio lower (P less than 0.05) in the daughters of the nondiabetic and diabetic probands were pooled, CHD in the proband was associated particularly with low apolipoprotein A1/B ratio. In conclusion, (1) the presence of NIDDM in the proband appears to be associated in siblings with more profound lipid and lipoprotein changes (especially low HDL cholesterol and high total triglycerides) than a history of CHD in the proband, (2) a history of CHD in the proband is associated in children with apolipoprotein changes favouring atherosclerosis (low apolipoprotein A1, high apolipoprotein B, low apolipoprotein A1/B ratio). Different effects of a history of NIDDM and CHD in the proband on lipid, lipoprotein and apolipoprotein levels in the first-degree relatives warrants more population-based studies.

Serum lipids and lipoproteins in middle-aged non-insulin-dependent diabetics.

Serum lipids and lipoproteins were measured in 277 non-insulin-dependent diabetics (NIDDs) and in 124 non-diabetic control subjects (65 males, 59 females), aged 45-64 years. Altogether 88 of the diabetics were treated with diet (48 males, 40 females), 134 with oral drugs (56 males and 49 females treated with sulphonylureas, 14 males and 15 females treated with a combination therapy of sulphonylurea drug and metformin) and 55 with insulin (17 males, 38 females). The postglucagon C-peptide concentration in insulin-treated diabetics exceeded 0.60 nmol/l. The diabetics had lower levels of HDL and HDL2 cholesterol and higher levels of total and VLDL triglycerides than non-diabetic control subjects irrespective of the mode of treatment. The HDL2 subfraction seemed to be alone responsible for the decrease of HDL cholesterol. In the whole group of diabetics body mass index had a significant negative correlation to HDL cholesterol and a positive correlation to total triglyceride concentration in both sexes but plasma glucose failed to show any consistent association to HDL cholesterol concentration. The difference in HDL cholesterol between diabetics and non-diabetics persisted after adjustment for age, physical activity, alcohol intake and body mass index. In conclusion, the dyslipoproteinaemia in non-insulin-dependent diabetes is principally characterized by decreased HDL and HDL2 cholesterol concentrations and by increased total and VLDL triglycerides. These manifestations of dyslipoproteinaemia are little influenced by the degree of glycaemia and obesity.

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 1 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 mumol/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.

Long-term association of cardiovascular risk factors with impaired insulin secretion and insulin resistance.

The study aim was to investigate the association of cardiovascular risk factors with insulin resistance and impaired insulin secretion in an 8-year prospective population study in nondiabetic subjects. Cardiovascular risk factors of 271 subjects aged 16 to 61 years were measured at baseline, and insulin sensitivity and acute-phase insulin secretion were assessed by an intravenous glucose tolerance test (IVGTT) and Bergman's minimal model 8 years later. In logistic regression analysis, baseline high-density lipoprotein (HDL) and very-low-density lipoprotein (VLDL) cholesterol (P < .001 and P = .006, respectively), total, low-density lipoprotein (LDL), and VLDL triglycerides (P = .004, P = .048, and P = .002, respectively), apolipoprotein A1 (P = .010), and uric acid (P < .001) were associated with insulin resistance after adjustment for age and the body mass index (BMI). Systolic blood pressure (P = .042) and VLDL cholesterol (P = .018) were associated with impaired insulin secretion after adjustment for age and the BMI. This 8-year longitudinal study demonstrates that dyslipidemia, high blood pressure, and uric acid are associated with insulin resistance, whereas high systolic blood pressure and VLDL cholesterol are associated with impaired first-phase insulin secretion.

Association of serum lipids and lipoproteins with plasma C-peptide concentration in non-insulin-dependent diabetic and non-diabetic subjects.

Serum lipids and lipoproteins were studied in 149 non-insulin-dependent diabetic subjects treated with diet or oral drugs (75 men, 74 women) and in 101 nondiabetic control subjects (49 men, 52 women) in relation to endogenous insulin secretion capacity measured by plasma C-peptide response to intravenous glucagon. Serum HDL- and HDL2-cholesterol concentrations were lower and VLDL-cholesterol and total and VLDL-triglyceride concentrations higher in subjects with high C-peptide response (above the median) than in subjects with low C-peptide response (lower or equal to median) both in diabetic and control subjects of both sexes. Adjustment for the effect of obesity abolished these differences in serum lipids and lipoproteins in diabetic subjects but not in control subjects. This may indicate that obesity has stronger influence on serum lipids in diabetic subjects than in nondiabetic subjects.

Inverse relationship of serum HDL and HDL2 cholesterol to C-peptide level in middle-aged insulin-treated diabetics.

Serum lipids and lipoproteins were measured in 170 insulin-treated diabetics (90 females, 80 males) and in 124 nondiabetic control subjects (59 females, 65 males) aged 45 to 64 years. Plasma C-peptide response to intravenous (IV) glucagon was measured in order to classify the patients according to their capacity of endogenous insulin secretion. In both sexes, HDL and HDL2 cholesterol were higher in diabetics with no C-peptide response than in controls, whereas diabetics with high C-peptide response (postglucagon C-peptide level greater than 0.60 nmol/L) showed lower levels of HDL and HDL2 than nondiabetic controls. When adjustment for age, alcohol consumption, physical activity, body mass index, and insulin dose was made by analysis of covariance, the highly significant difference in HDL and HDL2 cholesterol level between diabetics with no C-peptide response and diabetics with high C-peptide response still remained in both sexes. This study gives support to the hypothesis that elevated HDL and HDL2 cholesterol levels in insulin-treated diabetics are not explained by effects of treatment with exogenous insulin, but rather are associated with the type of diabetes characterized by deficient endogenous insulin secretion.

Clinical characteristics in the discrimination between patients with low or high C-peptide level among middle-aged insulin-treated diabetics.

We compared sensitivity, specificity and accuracy of selected clinical characteristics (age at diagnosis, initiation of permanent insulin therapy from diagnosis and degree of obesity) in the discrimination between diabetics with low or high fasting or post-glucagon C-peptide level in a population of 171 middle-aged insulin-treated diabetics (81 men, 90 women) living in East Finland. Individual clinical criteria were poor discriminators alone but their combinations gave high specificity for the low and high fasting and post-glucagon C-peptide classes. The specificity and the accuracy of combined criteria seemed to be somewhat higher among male than among female insulin-treated diabetics. The association between clinical characteristics and fasting or postglucagon C-peptide classes seemed to be similar.

Essential hypertension and insulin resistance in non-insulin-dependent diabetes.

A recent study has shown that young, lean, hypertensive subjects are more insulin resistant than corresponding normotensive subjects. Whether this finding can also be demonstrated in the presence of non-insulin-dependent diabetes mellitus (NIDDM) is not known. Therefore, the degree of insulin resistance was studied in 26 middle-aged hypertensive patients with NIDDM (11 men, 15 women) and 14 normotensive patients with NIDDM (eight men, six women) matched for age, metabolic control and the duration of diabetes, utilizing the glucose clamp technique. Non-obese NIDD patients (body mass index less than 27.0 kg m-2) with hypertension (n = 11) had significantly lower glucose disposal rates (GDRs) during the last 60 min of euglycaemic (5.5 mmol l-1) and hyperinsulinaemic (approximately 600 pmol l-1) clamp studies than NIDD patients without hypertension (n = 6) (782 +/- 94 vs. 1418 +/- 97 mumol m-2 min-1, P less than 0.05). In contrast, GDRs were similar in obese NIDD patients with (n = 15) and without (n = 8) hypertension (802 +/- 90 vs. 849 +/- 90 mumol m-2/min-1, respectively, P = NS). Basal hepatic glucose output, suppression of hepatic glucose production during hyperinsulinaemia and insulin secretion capacity did not differ between hypertensive and normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance.

We tested the hypothesis that insulin resistance, rather than high insulin level, is associated with lipid and lipoprotein changes favoring atherosclerosis independently of the glucose tolerance status. To this aim, 50 subjects with normal glucose tolerance, 28 subjects with impaired glucose tolerance, and 54 subjects with noninsulin-dependent diabetes (NIDDM) were studied. Subjects with low glucose disposal rate (GDR) or a high degree of insulin resistance as measured by the euglycemic hyperinsulinemic clamp technique had lower high density lipoprotein (HDL) cholesterol and higher total and very low density lipoprotein (VLDL) triglycerides than did subjects with high GDR (highest GDR tertile). These associations were independent of fasting insulin level and other confounding factors. In stepwise multiple linear regression analysis, GDR was the most important single variable associated with HDL cholesterol and VLDL triglyceride level independently of age, obesity, distribution of obesity (waist/hip ratio), 2-hour glucose level, and free fatty acid concentration. We conclude: 1) insulin resistance measured by the euglycemic clamp technique is associated with adverse lipid and lipoprotein changes favoring atherosclerosis not only in nondiabetic subjects (as shown in previous studies) but also in impaired glucose tolerance and NIDDM subjects; 2) the association of high insulin level with adverse lipid and lipoprotein changes indirectly reflects the association of insulin resistance with lipid and lipoprotein levels; and 3) HDL cholesterol and VLDL triglycerides are independently associated with insulin-mediated glucose uptake, which may indicate that these lipoproteins have separate sites of interaction with insulin action.

Repeatability of C-peptide response in glucagon stimulation test.

Measurement of the plasma C-peptide level before and after iv administration of 1 mg of glucagon was repeated four times in 10 elderly non-diabetic subjects and in 20 elderly non-insulin-dependent diabetics treated with diet or oral drugs to assess the repeatability of the C-peptide responses. Plasma C-peptide levels before and after glucagon administration and C-peptide glucose ratios in the four measurements did not differ significantly from test to test either in diabetic or non-diabetic subjects. The results of the present study indicate that the repeatability of C-peptide response to glucagon is very good both in non-insulin-dependent diabetics and in non-diabetic subjects.