Recessive inheritance of obesity in familial non-insulin-dependent diabetes mellitus, and lack of linkage to nine candidate genes

Segregation analysis of body-mass index (BMI) supported recessive inheritance of obesity, in pedigrees ascertained through siblings with non-insulin dependent diabetes mellitus (NIDDM). BMI was estimated as 39 kg/m2 for those subjects homozygous at the inferred locus. Two-locus segregation analysis provided weak support for a second recessive locus, with BMI estimated as 32 kg/m2 for homozygotes. NIDDM prevalence was increased among those subjects presumed to be homozygous at either locus. Using both parametric and nonparametric methods, we found no evidence of linkage of obesity to any of nine candidate genes/regions, including the Prader-Willi chromosomal region (PWS), the human homologue of the mouse agouti gene (ASP), and the genes for leptin (OB), the leptin receptor (OBR/DB), the beta3-adrenergic receptor (ADRB3), lipoprotein lipase (LPL), hepatic lipase (LIPC), glycogen synthase (GYS), and tumor necrosis factor alpha (TNFA).     

Association between duration of obesity and risk of non-insulin-dependent diabetes mellitus. The Sotetsu Study

The authors investigated the association between duration of obesity (ordinary obesity as body mass index (BMI) (kg/m2) > or = 25.0 and extreme obesity as BMI > or = 27.8) and the risk of diabetes mellitus. Male employees of a railway company, aged 30 years or older, observed for 10 years or more, free from serious disease conditions, with initial BMI <25.0, aged 30 years or more at the time diabetes was diagnosed, and with complete data, were examined by univariate and multivariate analyses (n = 1,598). Age-adjusted odds ratios for diabetes were significantly increased among males who were obese for 10-19.9 years and >20 years (odds ratios = 2.10 and 2.84 for ordinary obesity and 6.14 and 4.15 for extreme obesity, respectively). Additional adjustment for current obesity, physical activity, smoking, drinking, family history, and observation period did not change the findings remarkably. In conclusion, > or = 10 years duration of ordinary obesity or > or = 1 year of extreme obesity was an important predictor for diabetes independent of age, current obesity, physical activity, smoking, drinking, family history, and observation period.     

Caries in patients with non-insulin-dependent diabetes mellitus

OBJECTIVE: To describe intratrial differences in hind limb symmetry in healthy dogs at the trot, using noninvasive, computer-assisted, three-dimensional kinematic gait analysis. ANIMALS: 8 clinically normal large-breed adult dogs. PROCEDURE: Dynamic flexion and extension angles and angular velocities were calculated for the coxofemoral, femorotibial, and tarsal joints of dogs at the trot. Temporal and distance variables were computed. Essential Fourier coefficients were used to determine mean flexion and extension curves for all joints and to compare differences in movement between right and left hind limbs. Variances attributable to limb, dog, and trial were determined. RESULTS: Each joint had a characteristic pattern of flexion and extension movement that was used to compare intratrial symmetry of hind limb gait. Significant differences were not detected in temporal or distance variables between the right and left hind limbs. Significant differences were not noted in essential Fourier coefficients used to characterize coxofemoral, femorotibial, and tarsal joint angles and angular velocities, with the exception of the cosine-0 coefficient for coxofemoral angular velocity. Variation in joint angle and angular velocity measurements were attributable to individual dog and trial. Variation attributable to limb was negligible. CONCLUSIONS: Intratrial evaluation of right-left hind limb symmetry, using kinematic gait analysis, indicated objectively that hind limb movement is symmetrical at the trot in healthy large-breed dogs. CLINICAL RELEVANCE: Documentation of hind limb symmetry at the trot will help provide a basis for direct comparison of both hind limbs in future studies evaluating gait and treatment of dogs with musculoskeletal disease.     

Early endothelial alterations in non-insulin-dependent diabetes mellitus

Nude mice were given AlPcS2a (aluminum phthalocyanine disulfonate) and AlPcS4 (aluminum phthalocyanine tetrasulfonate) by intraperitoneal injections. After time intervals of 1-48 hours the mice were exposed to 150 mW cm-2 light at 670 nm and the phthalocyanine fluorescence was measured during light exposure. During the first few minutes of light exposure the phthalocyanine fluorescence of the skin of the mice increased by up to a factor of two, indicating lysosomal localization of the dye and permeabilization of the lysosomes. The process did not occur in the skin of dead mice, indicating that the process was dependent on oxygen.     

Effects of glycemic control on saliva flow rates and protein composition in non-insulin-dependent diabetes mellitus

Records from patients admitted to the surgical or medical department or examined in the respective outpatient departments in a Kuwaiti district hospital were reviewed retrospectively to discern the demographic characteristics of patients with complicated urinary tract infections (UTI), underlying conditions, pathogens and their antimicrobial susceptibility patterns. Kuwaiti nationals constituted the largest group, followed by Egyptians, which in the population of 225 patients studied comprised 41% and 27%, respectively; 65 of these 225 patients (29%) had urinary stones; 33 of the 92 Kuwaiti patients (36%) had diabetes mellitus; 38 of the 60 Egyptian patients (63%) had urinary stones and 18 had bilharziasis (30%). Pathogens were isolated 353 times from 225 patients. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and several other organisms in those patients with bilharziasis, urinary stones, and especially diabetes mellitus, displayed lower susceptibility frequencies to antimicrobials in comparison with other surgical and medical UTI isolates. Surgical and medical UTI organisms showed an overall higher antimicrobial resistance frequency than did UTI organisms from the maternity department or regional clinics. More than half of the population of Kuwaiti consists of expatriates from different countries. Such a population structure can exhibit peculiarities when health is considered. All this should be taken into consideration while dealing with disease management.     

Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus

Mechanisms for the cell-free activation of NADPH oxidase by sodium dodecyl sulfate (SDS) and arachidonate were compared in relation to their responsiveness to short chain diacylglycerols. The plasma membrane and cytosol prepared from guinea pig neutrophils were used for the cell-free system. The activation of NADPH oxidase by SDS was enhanced about 5- to 10-fold by 1,2-dioctanoylglycerol (diC8), but not by either 1,2-dihexanoylglycerol (diC6) or 1,2-didecanoylglycerol (diC10). However, none of these diacylglycerols potentiated the NADPH oxidase activation by arachidonate. The maximal extent of activation by the combination of SDS and diC8 was similar to that by arachidonate alone. In the presence of sufficient amounts of diC8 and SDS, GTP gamma S potentiated the activation of NADPH oxidase. The potentiating activity of diC8 was preserved in the membrane fraction, not in the cytosol fraction. These results suggest that arachidonate may possess the functions of both SDS and diC8 in the activation. In addition, diC8 and GTP gamma S seem to independently enhance the NADPH oxidase activation.     

Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus

OBJECTIVE: To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: A four-center randomized crossover trial. SETTING: Outpatient and inpatient evaluation in metabolic units. PATIENTS: Forty-two NIDDM patients receiving glipizide therapy. INTERVENTIONS: A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high-monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. MAIN OUTCOME MEASURES: Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels. RESULTS: The site of study as well as the diet order did not affect the results. Compared with the high-monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% (P < .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (P < .0001), and 9% (P = .02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks. CONCLUSIONS: In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable.     

Insulinoma in a patient with non-insulin-dependent diabetes mellitus

Insulinoma in a patient with pre-existing diabetes is exceedingly rare. Only a small number of well-documented cases have been reported in the world during the last 40 years. We describe a case with non-insulin-dependent diabetes mellitus who after seven years of sulfonylurea treatment experienced recurrent episodes of hypoglycemia. Endogenous hyperinsulinism was found and radiographical examination and transhepatic venous sampling confirmed an insulin secreting pancreatic tumor. After surgical excision of the tumor, patient was relieved from hypoglycemic attacks but required to initiate insulin injection for the treatment of hyperglycemia.     

Reduced myocardial flow reserve in non-insulin-dependent diabetes mellitus

OBJECTIVES: We analyzed myocardial flow reserve (MFR) in patients with non-insulin-dependent (type II) diabetes mellitus (NIDDM) without symptoms and signs of ischemia. BACKGROUND: Diminished MFR in diabetes has been suggested. However, it remains controversial whether MFR is related to glycemic control, mode of therapy or gender in NIDDM. METHODS: Myocardial blood flow (MBF) was measured at baseline and during dipyridamole loading in 25 asymptomatic, normotensive, normocholesterolemic patients with NIDDM and 12 age-matched control subjects by means of positron emission tomography and nitrogen-13 ammonia, after which MFR was calculated. RESULTS: Baseline MBF in patients with NIDDM ([mean +/- SD] 74.0 +/- 24.0 ml/min per 100 g body weight) was comparable to that in control subjects (73.0 +/- 17.0 ml/min per 100 g). However, MBF during dipyridamole loading was significantly lower in patients with NIDDM (184 +/- 99.0 ml/min per 100 g, p < 0.01) than in control subjects (262 +/- 120 ml/min per 100 g), as was MFR (NIDDM: 2.77 +/- 0.85; control subjects: 3.8 +/- 1.0, p < 0.01). A significantly decreased MFR was seen in men (2.35 +/- 0.84) compared with women with NIDDM (3.18 +/- 0.79, p < 0.05); however, no significant differences were found in terms of age, hemoglobin a1c and baseline MBF. MFR was comparable between the diet (2.78 +/- 0.80) and medication therapy groups (2.76 +/- 0.77) and was inversely correlated with average hemoglobin A1c for 5 years (r = -0.55, p < 0.01) and fasting plasma glucose concentration (r = -0.57, p < 0.01) but not age or lipid fractions. CONCLUSIONS: Glycemic control and gender, rather than mode of therapy, is related to MFR in NIDDM.     

Tumor necrosis factor-alpha; a possible pathogenic factor in obesity in insulin resistant and non-insulin-dependent diabetes mellitus?

The role of tumor necrosis factor (TNF)-alpha in the development of insulin resistance has repeatedly been emphasized in the past few years. The present paper summarizes the data (including the authors' observations as well) focusing on the potential role of TNF-alpha in the pathogenesis of obesity and non-insulin-dependent diabetes mellitus: alteration of insulin receptor function, lipid metabolism, expression of sulphonylurea receptors, all of them suggested to be related to the TNF-alpha. The potential clinical relevances are shortly reviewed.     

Breastfeeding and incidence of non-insulin-dependent diabetes mellitus in Pima Indians

BACKGROUND: Early exposure to cow's milk has been implicated in the occurrence of insulin-dependent diabetes mellitus but there is little information about infant-feeding practices and subsequent non-insulin-dependent diabetes mellitus (NIDDM). We examined the association between breastfeeding and NIDDM in a population with a high prevalence of this disorder, the Pima Indians. METHODS: Glucose-tolerance status was obtained from a 75 g oral glucose-tolerance test. A standard questionnaire given to mothers was used to classify infant-feeding practices for the first 2 months of life into three groups; exclusively breastfed, some breastfeeding, or exclusively bottlefed. The association between the three infant-feeding groups and NIDDM was analysed by multiple logistic regression. FINDINGS: Data were available for 720 Pima Indians aged between 10 and 39 years. 325 people who were exclusively bottlefed had significantly higher age-adjusted and sex-adjusted mean relative weights (146%) than 144 people who were exclusively breastfed (140%) or 251 people who had some breastfeeding (139%) (p = 0.019). People who were exclusively breastfed had significantly lower rates of NIDDM than those who were exclusively bottlefed in all age-groups (age 10-19, 0 of 56 vs 6 [3.6%] of 165; age 20-29, 5 [8.6%] of 58 vs 17 [14.7%] of 116]; age 30-39, 6 [20.0%] of 30 vs 13 [29.6%] of 44). The odds ratio for NIDDM in exclusively breastfed people, compared with those exclusively bottlefed, was 0.41 (95% CI 0.18-0.93) adjusted for age, sex, birthdate, parental diabetes, and birthweight. INTERPRETATION: Exclusive breastfeeding for the first 2 months of life is associated with a significantly lower rate of NIDDM in Pima indians. The increase in prevalence of diabetes in some populations may be due to the concomitant decrease in breastfeeding.     

Effects of weight cycling and metabolic control in male outpatients with non-insulin-dependent diabetes mellitus.

Examined the effects of losing and regaining or gaining and relosing body weight in weight cycling (WC) vs weight maintenance (WM) on metabolic control. Ss were 327 adult male outpatient veterans (mean age 62.8 yrs) with non–insulin-dependent diabetes mellitus who were followed an average of 3.4 yrs. When compared with WM, WC, whether defined as a categorical or as a continuous variable, was not associated with deficits in metabolic control or increased need for hypoglycemic medication. Ss who weight cycled had fasting serum glucose and hemoglobin A1c levels comparable to those who remained within 10% of their initial body weights, and these levels of metabolic control were obtained with similar classes and dosages of hypoglycemic medication. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Frequency of diabetes in family members of probands with non-insulin-dependent diabetes mellitus

OBJECTIVES: To describe the prevalence of known diabetes in a multi-ethnic community in South Auckland, New Zealand, in relation to family history of diabetes and past history of diabetes in pregnancy. DESIGN: A cross-sectional, household survey comparing ascertainment with local general practice diabetes registers where they existed. SETTING: An inner-city community with a high proportion of Maori, Pacific Islands people and Europeans. SUBJECTS: A total of 55,518 residents (91% response). Comparison with diabetes registers showed 91% ascertainment of known diabetic residents. More detailed interviews with 176/214 (82%) Europeans, 286/336 (85%) Maori and 495/585 (85%) Pacific Islands people with known diabetes. Fifty subjects had insulin-dependent diabetes mellitus on clinical criteria and were excluded from analyses. MAIN OUTCOME MEASURES: Prevalence of diabetes. RESULTS: Those with non-insulin-dependent diabetes mellitus were more likely to have a diabetic mother than father (Europeans, 21.7% vs. 9.9%; Maori, 17.6 vs. 11.4%; Pacific Islands, 15.7 vs. 5.3%). Diabetic women had a similar likelihood of having a diabetic father as diabetic men but were 1.84 times as likely to have a diabetic mother (95% CI, 1.27-2.69). Diabetic women with past diabetes in pregnancy had 2.05 (95% CI, 1.01-4.15) times the chance of a diabetic offspring as women who had not had past diabetes in pregnancy, who in turn had 2.69 (95% CI, 1.17-6.18) times the likelihood of having a diabetic offspring as diabetic men. CONCLUSIONS: The mother is a more important conduit for inheritance of diabetes than the father in these three ethnic groups. A history of diabetes in pregnancy confers an extra risk to the offspring above this usual maternal excess.     

Is low birth weight a risk factor for development of non-insulin-dependent diabetes mellitus?

Different lines of evidence indicate that low birth weight and insufficient intrauterine nutrition may represent significant risk factors for the development of late onset non-insulin dependent diabetes mellitus (NIDDM). The evidence includes epidemiological studies, animal studies and metabolic studies of non-diabetic subjects with low birth weight. Insufficient intrauterine nutrition may induce a variety of abnormalities of metabolism in different tissues including muscle, liver, pancreas and adipose tissue; which can all in turn be related to known defects of glucose metabolism involved in the development of hyperglycaemia in NIDDM. Future studies should address the important question as to which roles genetics versus intrauterine and postnatal factors play in the etiology of late onset NIDDM in the general population. This may have important implications for which initiatives that should be applied to prevent NIDDM.     

Epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM)

The diagnostic criteria of the US National Diabetes Data Group and the World Health Organization have stimulated a major increase throughout the world in epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). They have established that much of NIDDM is undiagnosed, that onset of NIDDM occurs at least 7 y before its diagnosis, and that significant morbidity and premature mortality occur in subjects with undiagnosed diabetes. New studies have shown that rural or traditional-living populations are experiencing a major increase in the burden of NIDDM as they move to urban or nontraditional situations, often with 5- to 10-fold increases in NIDDM prevalence. Epidemiologic studies have documented that major risk factors for NIDDM include increasing age, greater obesity, longer duration of obesity, unfavourable body fat distribution, physical inactivity, and hyperinsulinemia. All these factors interact with unknown genetic factors to produce NIDDM. Studies have shown that genes for diabetes, as yet undetermined, are a necessary cause of NIDDM. Hyperinsulinemia exists in childhood in populations at high risk for NIDDM. Stimulated by obesity, upper body obesity, and physical inactivity, insulin resistance develops, accompanied by impaired glucose tolerance. The pressure of the NIDDM risk factors continues this process of insulin resistance/hyperinsulinemia/hyperglycemia, until glucose toxicity to the beta cell results in inability to secrete sufficient insulin, resulting in decompensated fasting hyperglycemia.     

Endothelium-dependent relaxation in peripheral vasculature and kidney of non-insulin-dependent diabetes mellitus

Desmopressin (DDAVP), an AVP.V2-receptor agonist, evokes endothelium-dependent relaxation (EDR) due to nitric oxide (NO), EDR factor (EDRF) in the systemic vasculature, and glomerular afferent arterioles via AVP receptor(s). Glyceryl trinitrate (GTN) causes endothelium-independent (nonreceptor-mediated) vasodilation. We elucidated the possible involvement of EDRF in early non-insulin-dependent diabetes mellitus (NIDDM) and glomerular hyperfiltration (GHF) by DDAVP and GTN infusions. Patients with advanced DM nephropathy (DM.Np) (n = 7) were also examined. DDAVP and GTN decreased the mean blood pressure in DM with GHF (DM + GHF) and without GHF (DM-GHF) greater than that in normal subjects (N), without any difference in the heart rate changes in any group. Plasma levels of cGMP, a cellular messenger of NO, were significantly increased by DDAVP and GTN with a similar increment in each group. DDAVP caused a significant increase in urinary cGMP excretion in each group with a similar increment in each group. However, it caused a transient increase in creatinine clearance only in DM + GHF although GTN did not, and an exaggerated excretion of urinary albumin in early NIDDM, especially in DM+GHF, without a change in beta 2-microglobulin excretion. In contrast, in DM.Np GTN caused a decrease in blood pressure and an increase in plasma cGMP levels, but DDAVP did not. In conclusion, in peripheral vasculature and kidney, an enhanced sensitivity of vascular smooth muscle to NO is present in early NIDDM. The exaggerated dilation of glomerular afferent arterioles by preferentially produced NO in in situ, which causes a rise in PGC, might be partly responsible for the glomerular hyperfiltration and subsequently the increase in the glomerular protein permeation of DM+GHF. However, in peripheral blood vessels of DM.Np EDR is impaired. Thus, EDR seems to change with the development of NIDDM.     

The computer support of hypoglycemic therapy in non-insulin-dependent diabetes mellitus

Computer program designed by the authors and described in the article is realized as a reference system providing data on combinations of drugs used for diabetes mellitus. The system supplies information on hypoglycemic effects of representatives from each of three groups (insulins, sulfonamides, biguanides) administered both separately and in association with second drug selected by user. Interface of the system (drug menus and output windows) is friendly and demand no special training and operating skill. The program is written in C language and compiled as a single executable module for IBM-compatible personal computers.