Renal disease in noninsulin-dependent diabetes mellitus

Diabetic nephropathy now accounts for approximately one-third of all patients who develop end-stage renal disease. The estimated cost to supply renal replacement therapy for this population now exceeds $750 million. The relatively recent realization that half of these individuals suffer from noninsulin-dependent diabetes mellitus has sparked increased interest in attempts to understand the pathologic processes involved and how they may be similar or different from those alterations seen in insulin-dependent diabetes mellitus. Basic and clinical investigation continues in an attempt to solve the puzzle of pathogenesis, as well as answer questions about the clinical usefulness of microalbuminuria and the appropriate management of hypertension in this population.     

Dynamics of lipid peroxidation in patients with noninsulin-dependent diabetes mellitus

The time course of erythrocytic lipid peroxidation (LP) was studied in 55 patients with insulin independent diabetes mellitus aged 40 to 60 years LP was assessed by the content of malonic dialdehyde (MDA) and peroxidative hemolysis of erythrocytes (PHE). During diabetic decompensation LP activity was increased, especially in the presence of lower limb angiopathies. The authors assumed an idea of the involvement of LP products in the pathogenesis of vascular lesions. Diabetic compensation did not cause normalization of LP activity however the use of antioxidant (alpha-tocopherol acetate) led to a significant decrease in LP activity which can be of importance for the treatment of the early stages of diabetic angiopathies.     

How insulin resistant are patients with noninsulin-dependent diabetes mellitus?

The study was carried out to quantify the ability of physiological increases in the plasma insulin concentration to stimulate glucose disposal above basal levels in 25 normal subjects and 25 patients with noninsulin-dependent diabetes mellitus (NIDDM). Patients were sex, age, and weight matched, and glucose disposal was determined under basal conditions (plasma insulin, approximately 10 microU/ml) and after plasma insulin levels had been increased to approximately 90 microU/ml. The mean (+/- SEM) glucose disposal rate was significantly greater (P less than 0.001) under basal conditions in patients with NIDDM (110 +/- 5 mg/m2 X min) than in individuals with normal glucose tolerance (77 +/- 4 mg/m2 X min). Glucose disposal rates increased in both normal subjects and NIDDM patients when plasma insulin concentrations were increased to about 90 microU/ml; however, the increment was much greater in normal subjects. Thus, glucose disposal only rose to a mean (+/- SEM) value of 145 +/- 7 mg/m2 X min in patients with NIDDM, representing an approximate 30% increase due to insulin. In contrast, a similar elevation of plasma insulin in normal subjects resulted in an increase in glucose disposal of approximately 300%, reaching a mean (+/- SEM) value of 310 +/- 24 mg/m2 X min. These results indicate that the defect in insulin-stimulated glucose uptake is significantly greater in patients with NIDDM than has previously been found.     

Effect of gemfibrozil treatment in sulfonylurea-treated patients with noninsulin-dependent diabetes mellitus

This study was initiated to 1) assess gemfibrozil's ability to lower plasma triglyceride (TG) concentration in patients with NIDDM, and 2) determine whether this effect was associated with any changes in glycemic control. Measurements were made of mean hourly plasma glucose, insulin, TG, and FFA concentrations from 1200-1600 h in response to a test meal; hepatic glucose production (HGP); insulin-stimulated glucose uptake during a hyperinsulinemic glucose clamp study (MCR); and fasting plasma lipoprotein TG and cholesterol concentrations in 12 patients with NIDDM before and 3 months after gemfibrozil treatment. Although ambient plasma TG and FFA concentrations fell significantly, plasma glucose, insulin, HGP, concentrations fell significantly, plasma glucose, insulin, HGP, and glucose MCR did not change. However, when patients were divided into two groups, those with fasting plasma glucose levels above 9 mmol/L (fair control) and those with levels below 9 mmol/L (good control), a different phenomenon was observed. Patients in fair control had significant decreases in mean hourly plasma concentrations of glucose (15.1 +/- 1.7 to 12.6 +/- 0.9 mmol/L; P less than 0.001), insulin (523 +/- 59 to 471 +/- 75 pmol/L; P less than 0.001), FFA (652 +/- 150 to 504 +/- 76 mumol/L), and HGP (9.5 0.4 to 8.1 +/- 0.4 mumol/kg.min; P less than 0.005), and an increase in glucose MCR (2.63 +/- 0.49 to 3.72 +/- 0.54 mL/kg.min; P less than 0.07) in association with a fall in TG from 6.9 +/- 1.3 to 3.5 +/- 0.9 mmol/L (P less than 0.001). Although fasting low density lipoprotein cholesterol increased (1.8 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.05), the ratio of total to high density lipoprotein cholesterol decreased (6.84 +/- 0.88 to 5.80 +/- 1.05; P less than 0.02). Despite a significant fall in mean hourly TG concentration (4.6 +/- 0.7 to 3.8 +/- 0.7 mmol/L; P less than 0.001), neither insulin, FFA, HGP, nor glucose MCR changed in patients in good control. Furthermore, the mean hourly plasma glucose concentration increased from 9.2 +/- 0.7 to 11.7 +/- 1.4 mmol/L (P less than 0.001). Low density lipoprotein cholesterol also increased in this group (1.9 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.02), but, as before, the ratio of total to high density lipoprotein cholesterol decreased (8.15 +/- 1.93 to 6.36 +/- 1.03; P less than 0.02).     

Impaired salivary function in patients with noninsulin-dependent diabetes mellitus with xerostomia

To test this hypothesis, salivary function was measured by quantitative salivary scintigraphy in noninsulin-dependent diabetes mellitus (NIDDM) patients, as well as in age- and sex-matched controls for comparison. Seventy-two patients with NIDDM history of over 10 years and 36 healthy age- and sex-matched controls were enrolled in the study. All of the 72 NIDDM patients had good blood sugar control. None presented with autonomic neuropathy. These 72 NIDDM patients were separated into two subgroups. Group 1: 36 patients with xerostomia and Group 2: 36 patients without xerostomia. After intravenous injection of 5mCi Tc-99m pertechnetate, sequential images at 1 min/frame were acquired for 30 min. The 1st and 15th minute uptake ratios (UR) were calculated from the tracer uptakes in the four major salivary glands over the background regions of interest. Saliva excretion was stimulated by one tablet of 200 mg ascorbic acid given orally 15-min postinjection of the tracer. Then, the maximal excretion ratios (ER) of the four major salivary glands after sialagogue stimulation were calculated. Significantly poorer salivary function was found, represented by significantly decreased UR and ER values, in 36 NIDDM patients with xerostomia, when compared with 36 NIDDM patients without xerostomia and 36 healthy controls, via objective and quantitative salivary scintigraphy. It has been speculated that impaired salivary function contributes to NIDDM with xerostomia. However, further studies with a larger series of NIDDM patients are necessary to confirm our findings.     

Apolipoprotein-E2 and hyperlipoproteinemia in noninsulin-dependent diabetes mellitus

The association of apolipoprotein-E2 (apoE2) with hyperlipoproteinemia (HLP) was investigated in 23 noninsulin-dependent diabetes mellitus patients with apoE2 and 24 nondiabetic controls with apoE2. The frequency of HLP was significantly higher in diabetic subjects with apoE2 (73.9%) than in nondiabetic controls (37.5%). HLP in nondiabetic subjects with apoE2 included only type IV (n = 9), whereas HLP in diabetic subjects with apoE2 included type IIb (n = 1), type III (n = 7), and type IV (n = 9). Diabetic patients with apoE2 were characterized by increased levels of plasma triglyceride, total cholesterol (chol), very low density lipoprotein (VLDL)-chol, and apoE and an increased VLDL-chol/VLDL-triglyceride ratio, i.e. the accumulation of remnants. In addition, fasting plasma glucose and hemoglobin-A1 levels were significantly higher in hyperlipoproteinemic diabetic patients with apoE2 than in normolipidemic diabetic patients with apoE2. It is concluded that diabetes (poor metabolic control) predisposes apoE2 (epsilon 2)-carrying subjects to HLP (particularly type III) and that apoE2 may be one factor linking diabetes with HLP and cardiovascular disease.     

2型糖尿病患者心血管自主神经功能与QT离散度

目的 :探讨非胰岛素依赖型糖尿病 (2型糖尿病 )患者心血管自主神经功能与 QT离散度 (Q Td)、JT离散度 (JTd)和室性心律失常发生的关系。方法 :2型糖尿病患者 31例 ,按照标准心血管自主神经功能试验的结果分成阳性者及阴性组 ,16例健康人为正常对照组。所有入选人员均测 QTd、JTd及 2 4h Holter心电监测 ,并进行心律失常分析和比较。结果 :2型糖尿病患者心血管自主神经功能异常的发生率为 5 4.8% ,其发生率与病程呈正相关 ,QTd与 JTd显著延长 ,室性心律失常的发生率较高。结论 :QTd和 JTd可作为一项 2型糖尿病自主神经功能异常者发生室性心律失常重要的预测指标     

Insulin resistance and hypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent diabetes mellitus

Plasma glucose, FFA, and insulin responses to an oral glucose challenge, plasma lipid and lipoprotein concentrations, and the ability of insulin to stimulate glucose disposal were measured in 35 nondiabetic sedentary and overweight subjects. The subjects were divided into 2 groups on the basis of the presence (n = 19) or absence (n = 16) of a history of a first degree relative with noninsulin-dependent diabetes. The 2 groups were similar in age, body mass index, waist to hip ratio, and maximal aerobic capacity. The results demonstrated that the ability of insulin to stimulate disposal of a glucose load was significantly reduced in the subjects with a positive family history of noninsulin-dependent diabetes. In addition, these individuals had significantly higher plasma triglyceride and very low density lipoprotein cholesterol concentrations. Since all environmental factors known to modify insulin action and very low density lipoprotein metabolism were equal in the 2 groups, these data suggest that the metabolic differences noted are likely to be genetic in origin.     

Lipolysis and gluconeogenesis from glycerol are increased in patients with noninsulin-dependent diabetes mellitus.

The rate of lipolysis (glycerol Ra), gluconeogenesis from glycerol, and its contribution to overall hepatic glucose production (glucose Ra) were determined in 10 patients with noninsulin-dependent diabetes mellitus (NIDDM) [body mass index (BMI) 27.2 +/- 1.0 kg/m2, fasting plasma glucose 10.3 +/- 1.2 mmol/L], and in 6 matched control subjects (BMI 27.3 +/- 1.1 kg/m2, fasting plasma glucose 5.3 +/- 0.3 mmol/L) using infusions of [3-3H]glucose (0-600 min) and [U-14C]glycerol (360-600 min). Glycerol Ra was increased in the patients with NIDDM (120 +/- 16 mumol/m2.min) compared to the normal subjects (84 +/- 9 mumol/m2.min, P less than 0.05). Gluconeogenesis from glycerol was 1.7-fold higher in the patients (96 +/- 16 mumol/m2.min) than in the normal subjects (56 +/- 10 mumol/m2.min, P less than 0.05), and explained 9 +/- 1% and 7 +/- 1% (NS) of total glucose Ra in patients with NIDDM and normal subjects, respectively. To determine whether these abnormalities are more pronounced in overweight patients with NIDDM, glucose and glycerol Ra were also determined in 5 obese patients with NIDDM (BMI 36.4 +/- 1.0 kg/m2, fasting plasma glucose 11.3 +/- 1.3 mmol/L). Glycerol Ra (154 +/- 26 mumol/m2.min) was again higher than in the normal subjects (P less than 0.05) but not different from that in the less obese patients with NIDDM. The rate of gluconeogenesis from glycerol (159 +/- 20 mumol/m2.min) was significantly higher in the obese than in the less obese patients with NIDDM (P less than 0.05) but its contribution to total glucose Ra (10 +/- 1%) was similar to that in the less obese patients with NIDDM. When all data were analyzed together, gluconeogenesis from glycerol (r = 0.57, P less than 0.01) but not lipolysis (r = 0.02, NS) correlated with the percentage of lipolysis diverted toward gluconeogenesis suggesting that the rate of gluconeogenesis from glycerol is regulated by intrahepatic mechanisms rather than by glycerol availability. Neither the rate of lipolysis nor the rate of glycerol gluconeogenesis correlated with BMI, serum triglyceride, or insulin concentrations. We conclude that gluconeogenesis from glycerol is increased in patients with NIDDM. This increase appears to be the consequence of both accelerated lipolysis and increased intrahepatic conversion of glycerol to glucose.     

Circulating adhesion molecules and carotid artery structural changes in patients with noninsulin-dependent diabetes mellitus

Hypertension and non insulin-dependent diabetes mellitus (NIDDM) are well-known risk factors for atherosclerotic disease. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) may exert a relevant role in the pathogenesis of atherosclerosis; their prognostic relevance has been recently demonstrated. The aim of the study was to investigate possible inter-relation between circulating adhesion molecule levels, carotid artery structure and endothelial function in 15 patients with NIDDM, as well as in 15 patients with both NIDDM and essential hypertension (NIDDM+EH) compared with 15 normal subjects (NS) and 15 euglycaemic patients with EH, matched for age, sex and body weight. All subjects were submitted to a biopsy of the gluteal subcutaneous fat. Small arteries were dissected and mounted on a micromyograph, and the media-to-lumen (M/L) ratio was then calculated. Carotid artery structure was investigated by Doppler ultrasound. Endothelial function was evaluated by investigation of the flow-mediated dilatation (FMD) of the brachial artery. ICAM-1 and VCAM-1 plasma levels were measured by ELISA. ICAM-1 and VCAM-1 plasma levels were significantly greater and FMD smaller in EH, NIDDM and NIDDM+EH than in NS, but no difference was observed among the three pathological groups. Carotid artery structural changes were more pronounced in NIDDM+EH. No significant difference was observed among NIDDM, EH and NS. The M/L ratio of subcutaneous small resistance arteries was significantly greater in NIDDM+EH than in NIDDM or EH. NS had a smaller M/L ratio than the other groups. Significant correlations were observed between ICAM-1 plasma levels and indices of carotid artery structure in diabetic patients. However, the relations were close only in NIDDM+EH. In conclusion, our data suggest that NIDDM+EH may present more pronounced vascular structural alterations than NIDDM, and that adhesion molecules plasma levels are closely inter-related with carotid artery structural alterations, at least in NIDDM+EH, but not with M/L ratio of small resistance arteries.     

Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus

Plasma glucose, insulin, FFA, glucagon, and GH concentrations were measured over an 8-h period in normal subjects and patients with noninsulin-dependent diabetes mellitus (NIDDM). Meals were consumed at 0800 h (20% of daily calories) and noon (40% of daily calories), and measurements were made hourly from 0800-1600 h. Day-long plasma glucose, insulin, and FFA concentrations were higher than normal (by two-way analysis of variance) in patients with NIDDM, whether obese or nonobese. In addition, day-long plasma glucagon concentrations were also higher than normal (by two-way analysis of variance) in both nonobese and obese patients with NIDDM. Furthermore, direct relationships were found between the total plasma glucagon response from 0800-1600 h and total plasma glucose (r = 0.57; P less than 0.001) and FFA (r = 0.30; P less than 0.06) responses. In contrast, plasma GH levels were not increased in patients with NIDDM. These data demonstrate that ambient plasma concentrations of both glucose and FFA are higher in patients with NIDDM, despite the fact that coexisting plasma insulin levels are equal to or higher than normal. The higher day-long plasma glucagon levels in patients with NIDDM may contribute to their higher plasma glucose and FFA concentrations.     

Prevalence of dyslipoproteinemias among diabetes mellitus patients

The blood levels of total cholesterol, triglycerides, HDL cholesterol were determined in 330 patients with Type I and II diabetes mellitus (DM) and in 400 persons with the normal glucose tolerance test (GTT). On a curve of the distribution of values of total cholesterol, triglycerides, HDL cholesterol the upper 10% values were regarded as hypercholesterinemia (HCS) and hypertriglyceridemia (HTG) and the lower 10% values as hypo-alpha-cholesterinemia (hypo-alpha-CS). The prevalence of dyslipoproteinemia was shown to be much higher in the DM patients than in the healthy persons resulting from a more frequent development of HCS, HTG and hypo-alpha-CS in the patients. Some peculiarities of the prevalence of dyslipoproteinemia with relation to a DM type were revealed. It was shown that in Type I DM the prevalence of HCS and HTG was much higher than that in the persons with the normal GTT whereas the frequency of hypo-alpha-CS in both groups was the same. In patients with Type II DM as compared to the control group not only HCS and HTG but also hypo-alpha-CS were much more frequent. Moreover, the prevalence of HTG and hypo-alpha-CS in Type II DM was much higher than in Type I DM. Since dyslipoproteinemias were a risk factor in the development of atherosclerosis and coronary heart disease, one might assume that their greater prevalence among DM patients would determine patients' greater predisposition to atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disproportionately elevated proinsulin in Pima Indians with noninsulin-dependent diabetes mellitus

Fasting serum total immunoreactive insulin (IRI), true insulin, and true proinsulin (PI) were measured in 169 Pima Indians. The relationship of these variables to glucose tolerance, obesity, and parental diabetes was studied. Seventy-seven subjects had normal glucose tolerance, 46 had impaired glucose tolerance (IGT), and 46 had noninsulin-dependent diabetes mellitus (NIDDM) by WHO criteria. In subjects with normal glucose tolerance, the geometric mean ratio of PI to IRI (PI/IRI) was 10.8% (arithmetic mean, 12.5%), similar to that reported in other ethnic groups with lower prevalence rates of NIDDM. Parental diabetes had no effect on PI/IRI. Obese persons (body mass index, greater than or equal to 27 kg/m2) with normal glucose tolerance had PI/IRI of 9.3% compared with 16.3% for the nonobese (P less than 0.001), and PI/IRI was negatively correlated with body mass index (r = -0.34; P = 0.002). Proinsulin was disproportionately elevated in NIDDM (geometric mean PI/IRI, 19.9%; arithmetic mean, 23.6%), and the degree of elevation was related to the severity of hyperglycemia, but not the duration of diabetes. Subjects with IGT were more obese and had higher fasting plasma glucose (5.7 vs. 5.2 mmol/L; P = 0.025), true insulin (250 vs. 125 pmol/L; P less than 0.001), and PI concentrations (26 vs. 15 pmol/L; P less than 0.001) than those with normal glucose tolerance but similar mean PI/IRI (9.4 vs. 10.8%; P = 0.4). These findings indicate that Pima Indians with NIDDM have a disproportionate elevation of PI consistent with the hypothesis that beta-cell dysfunction associated with hyperglycemia leads to the release of proinsulin-rich immature granules.     

Inappropriately low erythropoietin response for the degree of anemia in patients with noninsulin-dependent diabetes mellitus

We investigated erythropoietin (Epo) response in a cohort of diabetic patients with various types of anemia to approach the pathogenesis of some cases of “unexplained” anemia encountered among diabetics. Serum Epo levels were determined totally in 747 evaluable subjects with normal renal and hepatic function, of whom 694 had anemia. Among anemic patients, 237 were diabetics, while among the 53 nonanemic persons, there were also 21 diabetics. Diabetic and nondiabetic subjects were uniformly balanced in relation to their demographic features and were categorized according to the etiology of their anemia. Hemoglobin (Hb) did not differ between diabetic and nondiabetic subjects in all the etiological groups and in the whole population. Diabetic patients had significantly lower serum Epo levels as compared to nondiabetics (36.5±61 vs 69.4±191 IU/ml, p<0.0001), and this was true for all etiologic groups of anemia with the exception of patients with myeloproliferative disorders and those with megaloblastic anemia. The natural logarithmic (ln)–Epo×Hb component was used as an index of response to anemia and was found to be significantly decreased in almost all subgroups of diabetic patients. Serum Epo levels were also negatively correlated with the percentage of glycosylated Hb, HbA1_C (r=−0.446), and the correlation was stronger with the ln of serum Epo (r=−0.638, p<0.001). Inappropriately low serum Epo level is a uniform feature in patients with type II diabetes mellitus and may represent a constitutive blunted response to anemia or an altered metabolic rate of Epo, probably as a result of abnormal glycosylation of the cytokine.     

Lessons from transgenic and knockout animals about noninsulin-dependent diabetes mellitus.

The application of transgenic techniques to alter gene expression in vivo has provided new models to evaluate the role of specific genes in the complex pathogenesis of noninsulin-dependent diabetes mellitus (NIDDM). In this review, we summarize methods used to create transgenic animals and highlight results from those models which have contributed to our understanding of the overall pathophysiology of NIDDM. Transgenic animal models have clearly demonstrated the requirement for normal insulin action in skeletal muscle, adipose tissue, and liver, as well as normal insulin secretion by the pancreatic beta-cell, in the maintenance of glucose homeostasis. In addition, these data confirm that isolated defects in single critical genes, including the insulin receptor, IRS-1, and glucokinase, may play a role in the development of some types of insulin resistance and NIDDM. However, it is likely that multiple additive defects, both genetic and acquired, are required to produce the full clinical syndrome typical of more common forms of NIDDM.     

Unexpected hospital admissions among patients with diabetes mellitus

In a search for a new way to recognize the patients who are at higher risk of unexpected hospitalizations, the characteristics of patients with diabetes mellitus were examined after their last office visit prior to hospitalization. Six characteristics contributed significantly in distinguishing 256 patients who were subsequently hospitalized from 512 patients who were not. The six characteristics included the following: frequent emergency room visits, low serum albumin level, cardiomegaly, anemia, hypotension, and hyperglycemia. The sensitivity of prediction was 43.2%, specificity was 77.4%, and the relative risk by odds ratio was 2.60:1. The intensity of care, as estimated by the level of the provider, and the intended intensity of care, as measured by the scheduled return-visit interval, were not clinically consistent with the magnitude of risk. The characteristics of patients at higher risk of unexpected hospitalizations were identified and provide a direction for increased intensity of ambulatory care.     

Diurnal variation of blood ketone bodies in insulin-dependent diabetes mellitus and noninsulin-dependent diabetes mellitus patients: the relationship to serum C-peptide immunoreactivity and free insulin

We examined whether the rise in ketone body concentration around midnight and in the early morning was due to the lack of free insulin (IRI) or excess of insulin counterregulatory hormones such as human growth hormone (hGH), cortisol and glucagon in noninsulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) patients and whether the monitoring of blood ketone body concentration was clinically useful as an index of metabolic control for deciding to increase or decrease the insulin dose in the treatment of diabetes mellitus. Serum levels of 3-hydroxybutyrate (3-OHBA), acetoacetate (AcAc) and 3-OHBA/AcAc ratio before breakfast were significantly increased in insulin-treated NIDDM patients with well-controlled fasting plasma glucose levels and IDDM patients compared to those in normal subjects. Mirror image diurnal changes were found between serum concentrations of 3-OHBA and serum C-peptide or free IRI in normal subjects and NIDDM patients treated with diet alone or sulfonylurea during the 24-hour daily profiles. However, there were no correlations between 3-OHBA and free IRI in the NIDDM patients treated with insulin and IDDM patients who had a much larger increase in the mean concentration of serum 3-OHBA at 6 a.m. caused by a low concentration of free IRI. Counterregulatory hormones were not increased in IDDM patients compared to normal subjects in the early morning. Cortisol/free IRI and hGH/free IRI molar ratios were significantly increased in NIDDM and IDDM patients compared to normal subjects in the early morning, but glucagon/free IRI molar ratio was not changed between IDDM and normal subjects. In conclusion, the early morning rising of ketone body concentration in insulin-treated diabetic patients, particularly IDDM patients, is due to the absolute lack of free IRI and/or the relative lack of free IRI to the levels of hGH or cortisol, and the monitoring of 3-OHBA is clinically useful as a more sensitive index of metabolic control.