Disease relevance of NIDDM1

• Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population [1].
• One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans [2].
• Impaired insulin-induced glucose uptake by extrahepatic tissue is hallmark of NIDDM patients who have or will develop hypertension and microalbuminuria [3].
• Other regions with LOD scores >2.0 included HDL linkage to chromosome 1q21-q23, where susceptibility loci for both familial type 2 diabetes and familial combined hyperlipidemia have been mapped, and to chromosome 2q in the region of the NIDDM1 locus [4].
• Our analysis of the relationship between the NIDDM 'high-risk' haplotype combination and extreme early onset obesity revealed no evidence for linkage and association [5].

Psychiatry related information on NIDDM1

• Increased physical activity is effective in preventing NIDDM, and the protective benefit is especially pronounced in persons at the highest risk for the disease [6].
• STUDY DESIGN: A 4-year observational study of 2235 patients (18 to 97 years of age) with hypertension, non-insulin-dependent diabetes mellitus (NIDDM), recent acute myocardial infarction, congestive heart failure, and depressive disorder sampled from HMO and FFS systems in 1986 and followed up through 1990 [7].
• Since this publication, whole genome screening has been performed in a variety of human polygenic diseases, including schizophrenia, bipolar affective disorder, non-insulin-dependent diabetes mellitus (NIDDM), inflammatory bowel disease, asthma and multiple sclerosis [8].
• It also is hypothesized that this thrifty genotype in these Indians may contribute to NIDDM when a sedentary life-style is adopted and food sources are constant [9].
• Several small clinical trials have addressed the hypothesis that NIDDM can be prevented by dietary modification, physical activity, or drug treatment [10].

High impact information on NIDDM1

• Finally, we show that in contrast to its short term potentiating effect on GSIS, long-term exposure of islets to high levels of fatty acids results in beta-cell dysfunction, suggesting that hyperlipidemia associated with obesity may play a causal role in the diminished GSIS characteristic of non insulin-dependent diabetes mellitus (NIDDM) [11].
• Evidence is presented that non-insulin-dependent diabetes mellitus (NIDDM) results from a failure on the part of pancreatic beta-cells to compensate adequately for the defect in insulin action in insulin-resistant individuals [12].
• Thus it is concluded that insulin resistance and its associated abnormalities are of utmost importance in the pathogenesis of NIDDM, hypertension, and coronary heart disease [12].
• A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2 [1].
• Using this method, we show that the interaction of genes on chromosomes 2 (NIDDM1) and 15 (near CYP19) makes a contribution to susceptibility to type 2 diabetes in Mexican Americans from Starr County, Texas [13].

Chemical compound and disease context of NIDDM1

• Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death [2].
• Coronary heart disease is an important cause of death in patients with non-insulin-dependent diabetes mellitus (NIDDM) and is particularly common in diabetic populations that have relatively high levels of plasma cholesterol [14].
• BACKGROUND: The metabolic effects and mechanism of action of metformin are still poorly understood, despite the fact that it has been used to treat patients with non-insulin-dependent diabetes mellitus (NIDDM) for more than 30 years [15].
• These data suggest that, like other populations at high risk for NIDDM such as Pima Indians and Micronesians, Mexican Americans have more hyperinsulinemia than can be accounted for by their adiposity [16].
• Troglitazone decreases insulin resistance and hyperglycemia in patients with non-insulin-dependent diabetes mellitus (NIDDM), but its effects on subjects without diabetes are not known [17].

Biological context of NIDDM1

• Here, our goal is to make inferences about the evolutionary forces shaping variation in genes in the NIDDM1 region and to investigate the population genetics models that may underlie the thrifty genotype hypothesis [18].
• Variants within the calpain-10 gene on chromosome 2q37 (NIDDM1) and relationships to type 2 diabetes, insulin resistance, and impaired acute insulin secretion among Scandinavian Caucasians [19].
• We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs [2].
• In the first reported positive result from a genome scan for non-insulin-dependent diabetes mellitus (NIDDM), Hanis et al. found significant evidence of linkage for NIDDM on chromosome 2q37 and named the putative disease locus NIDDM1 (Hanis et al. 1996. Nat. Genet. 13:161-166) [20].
• Thus, genetic variation in the HNF-1 alpha gene is not a common factor contributing to NIDDM susceptibility in white subjects of Danish ancestry [21].

Anatomical context of NIDDM1

• The storage of glucose as glycogen in skeletal muscle is frequently impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM) and their nondiabetic relatives [22].
• CONCLUSIONS: Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function [23].
• This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue [24].
• Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1) [25].
• Similarly, insulin exposure decreased insulin sensitivity and responsiveness of cultured adipocytes from obese and NIDDM patients [26].

Associations of NIDDM1 with chemical compounds

• Whereas the first three subgroups did not differ among themselves, they had significantly lower glucose utilization than did the normotensive NIDDM1 patients without microalbuminuria and nondiabetic controls (P < 0.01) [27].
• Seventy-five NIDDM patients attending the outpatient clinic of the Department of Internal Medicine of the University Hospital in Padua, Italy participated in the cross-sectional part of our study [3].
• These preliminary results suggest that partial replacement of complex carbohydrates with monounsaturated fatty acids in the diets of patients with NIDDM does not increase the level of LDL cholesterol and may improve glycemic control and the levels of plasma triglycerides and HDL cholesterol [28].
• CONCLUSIONS: Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone [29].
• Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM) [24].

Physical interactions of NIDDM1

• We conclude that insulin-resistant offspring of parents with NIDDM have reduced nonoxidative glucose metabolism and muscle glycogen synthesis secondary to a defect in muscle glucose transport/hexokinase activity prior to the onset of overt hyperglycemia [30].
• The purpose of the present study was to evaluate the effect of IGF-II on glucose transport in muscle of normal and obese patients with and without non-insulin-dependent diabetes mellitus (NIDDM), as well as to identify the receptor responsible for this action [31].
• We demonstrate that particular homozygous genotypes of TNF-alpha and GM and KM allotypes epistatically interact with HLA-DQalpha1(Arg 52) and contribute to an increased relative risk of NIDDM [32].

Regulatory relationships of NIDDM1

• The frequency of the inactive ALDH2 genotype was higher than that in the normal control subjects (P < 0.002) and that in the NIDDM control subjects (P < 0.003) [33].
• In contrast, platelet surface expression of CD36 in NIDDM (6.5 +/- 0.56 pmol/mg protein) was not significantly different from those of normal controls despite higher total content of CD36 (32.8 +/- 1.2, pmol/mg protein, p < 0 .01) [34].
• In response to 40 mU insulin, HKII mRNA in lean control subjects was increased 1.48 +/- 0.18-fold (P < 0.05) but failed to increase significantly in the obese (1.12 +/- 0.24) or NIDDM (1.14 +/- 0.18) groups [35].
• CONCLUSIONS: Gliclazide administration to NIDDM patients inhibits the increased adhesiveness of diabetic monocytes to endothelial cells and reduces the production of TNF-alpha by these cells [36].
• We conclude that 1. acute elevation of glucose by 5.5 mmol/L or more can activate PKC beta 2 translocation in controls and NIDDM patients in vivo irrespective of parameters of metabolic control [37].

Other interactions of NIDDM1

• These subjects were divided into four groups on the basis of BP levels and albumin excretion rate (AER): 28 normotensive normoalbuminuric (NIDDM1), 19 hypertensive normoalbuminuric (NIDDM2), 15 normotensive microalbuminuric (NIDDM3), and 13 hypertensive microalbuminuric patients (NIDDM4) [3].
• We found some evidence for linkage of T2DM to chromosome 2q approximately 20 cM proximal to the NIDDM1/CAPN10 locus [38].
• A recent random genome mapping study has localized a locus termed NIDDM2 that maps to the region of chromosome 12 that includes MODY3, one of the three genes responsible for maturity-onset diabetes of the young, a monogenic form of NIDDM characterized by early age of onset and autosomal dominant inheritance [21].
• Genetic variation in the hepatocyte nuclear factor-1 alpha gene in Danish Caucasians with late-onset NIDDM [21].
• None of the polymorphism carriers had both aminoacid variants and the total allelic frequency of IRS-1 polymorphisms was about three times higher in patients with NIDDM than in controls (p = 0.02) [39].

Analytical, diagnostic and therapeutic context of NIDDM1

• The protective effect of physical activity was strongest in persons at highest risk for NIDDM, defined as those with a high body-mass index, a history of hypertension, or a parental history of diabetes [6].
• We conclude that impaired glucose metabolism is common in the first-degree relatives of patients with NIDDM, despite their normal results on oral glucose-tolerance tests [40].
• In patients with NIDDM who are receiving oral hypoglycemic drug therapy, the addition of NPH insulin in the evening improves glycemic control in a manner similar to combination therapy with NPH insulin in the morning, a two-insulin-injection regimen, or a multiple-insulin-injection regimen, but induces less weight gain and hyperinsulinemia [41].
• The genetic dissection of NIDDM allowed us to map up to six independently segregating loci predisposing to hyperglycaemia, glucose intolerance or altered insulin secretion, and a seventh locus implicated in body weight [42].
• To investigate whether mutations in the gene for the beta 3-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis [24].

References