Genetics of insulin-dependent diabetes mellitus

IDDM is caused by autoimmune destruction of insulin-producing beta cells of the pancreas in genetically susceptible individuals. Although the incidence and prevalence if IDDM in Japan are much lower than those in Caucasian countries, the recurrence risk in siblings of IDDM probands is much higher than the population prevalence, indicating that IDDM is clustered in families even in Japan, where the incidence of the disease is the lowest in the world. The higher concordance rate in monozygotic twins than in dizygotic twins indicates that genetic factors contribute to the familial clustering of IDDM in Japan. Analysis of the HLA region revealed that susceptibility genes (IDDM1) consist of multiple components, those in class II DR and DQ regions and another in the class I region. Analysis in NOD mice, an animal model of IDDM, supports this observation: susceptibility genes (Idd1) are mapped to class II A and E regions, but the incidence of the disease is strongly affected by a gene or genes outside of this segment (Idd16). Studies in both humans and an animal model will clarify the genetic components of IDDM, facilitating prediction of the disease and the development of effective strategies for its prevention.     

The serum growth hormone-binding protein is reduced in young patients with insulin-dependent diabetes mellitus

Despite elevated serum concentrations of GH, longitudinal growth is stunted in a considerable number of children and adolescents with insulin-dependent diabetes mellitus (IDDM). To elucidate, whether reduced peripheral action of GH contributes to this phenomenon, GH-binding protein (GH-BP) activity was measured in 117 children and adolescents with IDDM (mean age 14.6 yr, range 4.5-28 yr) and 132 healthy controls (13.1 yr, 6.3-26 yr). Serum was incubated with 125I-GH, then chromatographed on a Sephacryl S200 column (1.8.100 cm), apparent binding of 125I-GH to GH-BP was corrected for the amount of endogenous GH present in the sample. GH-BP activity was significantly lower in IDDM patients, with a corrected binding of 16.8 +/- 0.6% compared to 21.3 +/- 0.7% in control children (mean +/- SE; P < 0.0001, Wilcoxon-test). Previous studies demonstrated that GH-BP is increased in healthy overweight children. In contrast, in IDDM children, GH-BP was reduced despite a moderate degree of overweight (z-score for weight: +0.94 +/- 0.12; mean +/- SE). Reduced serum GH-BP activity in IDDM children is further accentuated when compared to healthy children with a similar degree of overweight (22.8 +/- 0.5%; n = 44). Based on this novel finding, we conclude that decreased GH receptor density may explain reduced growth velocity despite increased secretion of GH in some IDDM children.     

Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 microg/kg and 20 microg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 PM to 8:00 AM) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU x kg(-1) x min(-1) from 8 to 10 AM and 1.5 mU x kg(-1) x min(-1) from 10 AM to 12 noon) incorporating [6,6 2H2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean +/- SEM) increased (40 microg/kg, 655 +/- 90 ng/mL, P < .001; 20 microg/kg, 472 +/- 67 ng/mL, P < .001; placebo, 258 +/- 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 AM to 8 AM) (40 microg/kg, 48 +/- 5 pmol/L, P = .01; 20 microg/kg, 58 +/- 8 pmol/L, P = .03; placebo, 72 +/- 8 pmol/L). The mean overnight GH level (40 microg/kg, 9.1 +/- 1.4 mU/L, P = .04; 20 microg/kg, 9.6 +/- 2.0 mU/L, P = .12; placebo, 11.3 +/- 1.7 mU/L) and GH pulse amplitude (40 microg/kg, 18.8 +/- 2.9 mU/L, P = .04; 20 microg/kg, 17.0 +/- 3.4 mU/L, P > .05; placebo, 23.0 +/- 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or beta-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 microg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.     

Coping styles in youths with insulin-dependent diabetes mellitus.

The relationships between two coping styles (i.e., use of personal and interpersonal resources; ventilation and avoidance) and two health outcomes (i.e., adherence and metabolic control) were evaluated in 135 youths with insulin-dependent diabetes mellitus (IDDM). Individual characteristics (i.e., age, duration of illness) and contextual variables (i.e., stress, family relations) were used to predict coping styles. Poor adherence to treatment, older adolescent age, and long duration of IDDM were correlated with ventilation and avoidance coping. Youths with short duration of IDDM were more likely to cope through the use of personal and interpersonal resources, although this strategy was not associated with health outcomes. A multiple regression analysis indicated that high ventilation and avoidance coping was predicted by high stress, low family cohesion, and older adolescent age. In addition, the interaction between family adaptability and duration of IDDM significantly predicted ventilation and avoidance coping. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Peripheral osteopenia in adult patients with insulin-dependent diabetes mellitus

Alterations in bone metabolism in diabetes mellitus is a topic of special interest. Bone blood flow is increased in the distal limb of diabetic patients, which is believed to increase osteoclastic activity. We measure bone mineral density using dual-photon absorptiometry in the distal lower limb, the femoral neck, and the lumbar spine in 41 IDDM patients and in 30 control persons. In the diabetic group there was a 10% reduction of bone mineral density in the femoral neck (p < 0.01) and a 12% reduction in the distal limb (p < 0.001) compared with the control group. No significant difference was found in the lumbar spine (p = 0.22). Our data yield incidence for peripheral osteopenia in IDDM-patients, independent of any systemic bone disease such as osteoporosis. A link between decreased bone mineral density and diabetic neuropathy has been observed for the femoral neck (p < 0.001), but not for the distal limb or axial skeleton. Whether there is a common aetiological link or a casual connection between diabetic neuropathy and bone mineral density has still to be determined.     

Insulin edema in three adolescents with insulin-dependent diabetes mellitus

Three female patients with a previously poorly controlled Insulin Dependent Diabetes Mellitus (IDDM), without evidence of cardiovascular, hepatic or renal dysfunction, developed generalized edema after a substantial increase in their insulin dosage. Edema resolved in 2-3 weeks, without specific therapy. Our patient's findings met the criteria of diagnosis of insulin edema. Insulin edema during IDDM is an uncommon complication of insulin therapy (1/400) and its pathogenesis is not clarified so far; it is a transient and self-limiting condition. The diagnosis is based on exclusion of all other major causes of edema.     

New developments in treating children with insulin-dependent diabetes mellitus

A number of new developments in the management of insulin-dependent diabetes mellitus have occurred in the past several years. Primary care providers including pediatric nurse practitioners need to be aware of these developments so that they can work effectively with specialty providers in caring for children with insulin-dependent diabetes mellitus. This article discusses the implications of the Diabetes Control and Complications Trial for children and adolescents, the Diabetes Prevention Trial-Type I, and several other recent developments in caring for children with insulin-dependent diabetes mellitus.     

Relative nocturnal hypertension in children with insulin-dependent diabetes mellitus

Twenty-four-hour blood pressure and heart rate measurements were carried out in 14 newly diagnosed diabetics and in 28 diabetics with 5-13 years' duration of the disease; 8 healthy children were used as controls. Mean arterial blood pressure increased at night in 5, decreased slightly (less than 10%) in 5 and decreased markedly (more than 10%) in 18 diabetics with longer duration of the disease. The diurnal-nocturnal differences in heart rates were significantly lower in diabetics with relative "nocturnal hypertension" compared to the control group (p < 0.05). A significant negative correlation was found between maximal arterial blood pressure during physical exercise and the diurnal-nocturnal differences in mean arterial blood pressure in diabetics (r = -0.58; p < 0.02). In conclusion, we found elevated nocturnal blood pressure in a subgroup of children with longer duration of diabetes and without increased albumin excretion. However, longitudinal studies of blood pressure profiles are needed to identify the candidates for diabetic vasculopathy among diabetic children.     

Prevalence and magnitude of osteopenia associated with insulin-dependent diabetes mellitus

Effects of bilateral chemical inactivation of the nucleus tractus solitarius (NTS) by microinjection of kainic acid (KA) on fluid and NaCl absorption across the jejunum were examined in anesthetized Sprague-Dawley rats. Jejunal fluid and NaCl absorption was measured in a jejunal loop before and after the microinjection of artificial cerebrospinal fluid (aCSF) or KA into the NTS. Net fluid and NaCl absorption was not altered by a microinjection of aCSF. However, net fluid (from 1.12 +/- 0.07 to 1.66 +/- 0.06 ml/30 min) and NaCl (Na+ from 164.5 +/- 10.1 to 243.3 +/- 7.1 muEq/30 min; and Cl- from 175.9 +/- 7.5 to 260.8 +/- 6.5 muEq/30 min) absorption was significantly increased by the chemical inactivation of the NTS. To examine the efferent mechanism of the increased net absorption induced by the NTS inactivation, mesenteric nerve activity (MNA) was measured before and after the inactivation of the NTS. MNA was significantly increased by 165.9 +/- 74.2% after the bilateral inactivation of the NTS. Furthermore, absorption experiments were conducted in rats with pretreatment of atropine (acetylcholine-antagonist) or yohimbine (specific alpha 2-antagonist). In atropine treated rats, net jejunal absorption was significantly increased by the inactivation of the NTS. However, the increase in net absorption induced by the inactivation of the NTS was completely abolished by pretreatment with yohimbine. These results suggest that the NTS has a tonic suppression on jejunal absorption through alpha 2-adrenergic mechanism.     

Elevated concentrations of circulating adhesion molecules and their association with microvascular complications in insulin-dependent diabetes mellitus

To better understand potential associations of circulating adhesion molecules (cAMs) with diabetic microangiopathy, circulating serum concentrations of intercellular adhesion molecule-1 (cICAM-1), vascular cell adhesion molecule-1 (cVCAM-1), and endothelial leukocyte adhesion molecule-1 (cELAM-1) were determined in patients with insulin-dependent diabetes mellitus (IDDM) (n = 70) presenting with varying degree of metabolic control and status of diabetic late complications, and were compared with age-matched healthy subjects (n = 70) in a cross-sectional study. Concentrations of cICAM-1 and cVCAM-1 were elevated in IDDM vs. age-matched controls (cICAM-1: 276 +/- 71 vs. 212 +/- 57 ng/mL; P < 0.0001; cVCAM-1: 781 +/- 245 vs. 615 +/- 151 ng/mL; P < 0.0001), whereas cELAM-1 did not differ between the groups (cELAM-1: 50 +/- 25 vs. 46 +/- 23 ng/mL, P = 0.31). The levels of cVCAM-1 were more markedly elevated in IDDM patients with diabetic retinopathy (n = 32) than in those without (n = 38) (cVCAM-1: 848 +/- 281 vs. 724 +/- 197 ng/mL, P < 0.05), as well as in patients with micro- or macroalbuminuria (n = 10) vs. those without (n = 60) (cVCAM-1: 947 +/- 256 ng/mL vs. 753 +/- 234 ng/mL, P < 0.05), whereas no difference in cICAM-1 and cELAM-1 was apparent regarding the clinical status of diabetic microangiopathy. No correlations were found between hemoglobin A1e and cAMs in the individual subgroups of patients and healthy subjects. Interestingly, however, low density lipoprotein cholesterol correlated with cVCAM-1 (r = 0.38, P = 0.03) in IDDM patients with diabetic microangiopathy (n = 33), but not in healthy controls or patients without microangiopathy (n = 37). Analyzing the pooled data of diabetic patients and healthy subjects (n = 140), concentrations of cICAM-1 were markedly related to cVCAM-1 (r = 0.45, P < 0.0001) and cELAM-1 (r = 0.31, P < 0.0002), whereas cVCAM-1 was related less to cELAM-1 (r = 0.19, P = 0.03), respectively. We conclude that, irrespective of actual metabolic control, serum concentrations of cICAM-1 and cVCAM-1 but not cELAM-1 are elevated in patients with IDDM, reflecting ongoing endothelial cell stimulation and leukocyte activation. More specifically, more marked elevation of cVCAM-1 may even hint at clinically manifest diabetic microangiopathy.     

Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) is a disease that results from autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. The autoimmune response against islet beta-cells is believed to result from a disorder of immunoregulation. According to this concept, a T helper 1 (Th1) subset of T cells and their cytokine products, i.e. Type 1 cytokines--interleukin 2 (IL-2), interferon gamma (IFNgamma), and tumor necrosis factor beta (TNFbeta), dominate over an immunoregulatory (suppressor) Th2 subset of T cells and their cytokine products, i.e. Type 2 cytokines--IL-4 and IL-10. This allows Type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Type 1 cytokines activate (1) cytotoxic T cells that interact specifically with beta-cells and destroy them, and (2) macrophages to produce proinflammatory cytokines (IL-1 and TNFalpha), and oxygen and nitrogen free radicals that are highly toxic to islet beta-cells. Furthermore, the cytokines IL-1, TNFalpha, and IFNgamma are cytotoxic to beta-cells, in large part by inducing the formation of oxygen free radicals, nitric oxide, and peroxynitrite in the beta-cells themselves. Therefore, it would appear that prevention of islet beta-cell destruction and IDDM should be aimed at stimulating the production and/or action of Type 2 cytokines, inhibiting the production and/or action of Type 1 cytokines, and inhibiting the production and/or action of oxygen and nitrogen free radicals in the pancreatic islets.     

The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes

The type 1 copper in Pseudomonas aeruginosa azurin was studied by electron paramagnetic resonance (EPR) spectroscopy at low microwave frequencies. Partially resolved ligand hyperfine structure was observed in the perpendicular region of the spectra at both S-band (2.4 GHz) and L-band (1.1 GHz). A trial and error method, requiring several hundred simulations, has been used to simulate the low frequency EPR data and yield an optimum value of 30 MHz for ACUx, more than one half that previously reported. The fit between the simulated and experimental data is sensitive to changes in the Euler angles and, in particular, to the angle alpha which rotates the Cu A-tensor about the z-axis. Thus, the A- and g-tensors for copper in P. aeruginosa azurin do not appear to be coincident. A value for the Euler angle beta of at least 10 degrees does not disturb the fit between the simulated and experimental data. These studies demonstrate the advantage of evaluating EPR parameters from simulations at more than one frequency, especially at low frequencies where ligand superhyperfine structure may be resolved for type 1 copper.     

Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus

BACKGROUND: Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained. METHODS: We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years. RESULTS: In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5 +/- 2.9 and 12.6 +/- 2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3 +/- 2.3 vs 8.6 +/- 1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5 +/- 2.1 vs 9.0 +/- 2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric. CONCLUSIONS: Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.     

Retinopathy in African Americans and whites with insulin-dependent diabetes mellitus

BACKGROUND: The development and progression of diabetic retinopathy in African Americans with insulin-dependent diabetes mellitus is not known. METHODS: Two hundred subjects with insulin-dependent diabetes mellitus with duration of diabetes 16 years or less at first visit were studied; 58 were African Americans and 142 were whites. All had gradable stereoscopic color fundus photographs (seven standard fields) from at least two visits (mean time between first and second visit was 4.1 years). Subjects with hemoglobinopathy or proliferative retinopathy or subjects who had evidence of treatment for proliferative retinopathy at first visit were excluded. Masked grading of photographs was conducted using the modified Airlie House classification scheme. RESULTS: African Americans were older, heavier, had higher systolic blood pressure (all P < .05), and marginally higher hemoglobin A1 (HbA1) values (P = .06) than the whites at first visit. African Americans had a lower rate of two steps or more progression from preexistent retinopathy (19%) than whites (43%). Progression to proliferative retinopathy or treatment was similar by race. Multivariate analysis predicting development oe progression of retinopathy, while controlling for length of follow-up, found higher HbA1 (odds ratio [OR] = 2.15), longer duration of insulin-dependent diabetes mellitus (OR = 1.69), higher serum creatinine concentration (OR = 1.59), and white race (OR = 2.62) to be independent risk factors. CONCLUSIONS: These data suggest a previously unsuspected reduction in the adjusted risk for development and progression of retinopathy in African Americans. The reason for this apparently reduced risk are not known.     

Incidence and hospitalization patterns of insulin-dependent diabetes mellitus

Data from a statewide insulin-dependent diabetes mellitus (IDDM) registry in Rhode Island show that IDDM affects young adults (20-29 yr) as frequently as adolescents and teenagers (10-19 yr). Overall incidence less than 30 yr was 14/100,000 population. Peak incidence occurred at 10-14 yr (19/100,000 population). Poor diabetic control and infection accounted for 46-62% of hospitalizations among 275 known diabetic persons. Despite a 10-yr mean duration of diabetes, only 31% of hospitalized diabetic persons less than 30 yr of age reported ever having received outpatient diabetes education of two or more hours. Readmissions 1 yr after initial registration were more frequent for known (43%) than new-onset (18%) IDDM cases. Increased risk of readmission for both groups was associated with a poverty socioeconomic status. Total direct hospitalization costs for IDDM in persons under 30 yr of age in Rhode Island was $530,000 per year of $2,245 per patient.     

Growth and sexual maturation in children with insulin-dependent diabetes mellitus

Prediabetes, the interval preceding the clinical recognition of diabetes mellitus, is believed to consist of several months or years of beta-cell destruction associated with no clinically recognized signs other than possible increased growth velocity. This increased growth rate may be the result of increased insulin, increased growth hormone, or both. As insulin-dependent diabetes approaches clinical recognition, insulin deficiency becomes manifest as slowing of growth velocity and more obvious weight loss. If a prepubertal child has insulin-dependent diabetes mellitus, sexual maturation is frequently delayed and physical growth is adversely affected. Insulin is an anabolic hormone that regulates metabolic pathways involved in the production of protein, glycogen, and fat. The normal release of growth hormone and the hepatic production of insulin-like growth factor I is modulated by the action of insulin. The absence of physiologic insulin response leads to dysfunctional quantities of growth hormone, insulin-like growth factor I, and sex hormones, resulting in growth impairment and delayed sexual maturation. Delayed sexual maturation may cause concern because it has a major impact on growth and maturation of children. However, there is evidence that sex hormones have a stimulating effect on the tissue damage associated with chronic hyperglycemia. The loss of physiologic insulin release significantly affects physical growth, sexual maturation, and the chronic complications associated with insulin-dependent diabetes mellitus.