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M Lehto

Publications and source records attributed to M Lehto.

At least 37 records · Page 2Linked to original sources
PubMed1997

Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

Maturity-onset diabetes of the young (MODY) type 3 is a dominantly inherited form of diabetes, which is often misdiagnosed as non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM). Phenotypic analysis of members from four large Finnish MODY3 kindreds (linked to chromosome 12q with a maximum lod score of 15) revealed a severe impairment in insulin secretion, which was present also in those normoglycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with IDDM by lack of glutamic acid decarboxylase antibodies (GAD-Ab). Taken together with our recent findings of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM (NIDDM2), the data suggest that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response, that subsequently progresses to diabetes and underlines the importance of subphenotypic classification in studies of diabetes.

Adult↗
PubMed1997

Novel mutations and a mutational hotspot in the MODY3 gene.

Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) located on chromosome 12q. We have identified four novel HNF-1alpha missense mutations in MODY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in MODY3. We observed no HNF-1alpha mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes.

Chromosomes, Human, Pair 12↗
PubMed1996

Reconstruction of the chronically insufficient anterior cruciate ligament: long term results of the Eriksson procedure.

Thirty-two patients (26 men and 6 women) with symptoms due to chronic insufficiency of the anterior cruciate ligament were treated by reconstruction using the medial one-third of the patellar tendon. The average delay between injury and operation was 4.8 years. Prior to this, 28 operations had been carried out on the knees of 20 of the patients. At follow up, at an average of 6.6 years after reconstruction, 50% were satisfied subjectively with the end result, and 57% were excellent or good on the Lysholm score. The Lachman test showed that 50% were completely stable and none had severe laxity. The anterior drawer test was negative in 59% and only one had moderate laxity. The pivot shift was negative in 69% and only 2 were 2+ positive. Twenty-one of the 29 patients who were active in sport before their injury were able to continue their activity at the same or a reduced level.

Adult↗
PubMed1996

Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.

Non-insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide and is associated with severe metabolic defects, including peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion. Family studies point to a major genetic component, but specific susceptibility genes have not yet been identified-except for rare early-onset forms with monogenic or mitochondrial inheritance. We have screened over 4,000 individuals from a population isolate in western Finland, identified 26 families (comprising 217 individuals) enriched for NIDDM and performed a genome-wide scan using non-parametric linkage analysis. We found no significant evidence for linkage when the families were analysed together, but strong evidence for linkage when families were classified according to mean insulin levels in affecteds (in oral glucose tolerance tests). Specifically, families with the lowest insulin levels showed linkage (P = 2 x 10(-6)) to chromosome 12 near D12S1349. Interestingly, this region contains the gene causing the rare, dominant, early-onset form of diabetes MODY3. Unlike MODY3 families, the Finnish families with low insulin have an age-of-onset typical for NIDDM (mean = 58 years). We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.

Adult↗
PubMed1996

Polymorphism of the glycogen synthase gene in hypertensive and normotensive subjects.

Hypertension and non-insulin-dependent diabetes mellitus (NIDDM) are characterized by a strong genetic component and impaired ability to store glucose as glycogen in skeletal muscle. Impaired insulin activation and altered genetic control of muscle glycogen synthase, the rate-limiting enzyme for glucose storage in skeletal muscle, could provide an explanation for this insulin resistance. We examined whether there is an association between the glycogen synthase gene (Xba I polymorphism) and hypertension in 304 nondiabetic subjects. We examined glucose tolerance with an oral glucose tolerance test and glucose storage in skeletal muscle with the euglycemic insulin clamp technique in combination with indirect calorimetry. The Xba I A2 allele of the glycogen synthase gene was enriched in subjects with hypertension and a family history of NIDDM (48%) compared with normotensive subjects without a family history of NIDDM (6%, P < .0001). The presence of the A2 versus the A1 allele was associated with decreased rates of insulin-stimulated glucose storage in hypertensive subjects (11.2 +/- 2.3 versus 16.9 +/- 2.6 mumol/kg lean body mass per minute, P = .029) but not in normotensive subjects (28.0 +/- 4.6 versus 29.6 +/- 3.7 mumol/kg lean body mass per minute). In conclusion, Xba I polymorphism of the glycogen synthase gene identifies a subgroup of hypertensive subjects with a family history of NIDDM. The data suggest that a locus in the glycogen synthase gene region on chromosome 19 may serve as a "thrifty gene," increasing susceptibility for insulin resistance when exposed to other environmental or genetic factors.

Adult↗
PubMed1995

Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns.

BACKGROUND: Because visceral obesity predicts insulin resistance, we studied whether alterations in the gene encoding for the beta 3-adrenergic receptor in visceral fat are associated with insulin resistance. METHODS: We studied the frequency of a cytosine-to-thymidine mutation that results in the replacement of tryptophan by arginine at position 64 (Trp64Arg) of the beta 3-adrenergic receptor by restriction-enzyme digestion with BstOl in 335 subjects from western Finland, 207 of whom were nondiabetic and 128 of whom had non-insulin-dependent diabetes mellitus (NIDDM). We also determined the frequency of the mutation in 156 subjects from southern Finland. Sensitivity to insulin was measured by the hyperinsulinemic-euglycemic clamp technique in 66 randomly selected nondiabetic subjects. RESULTS: In the subjects from western Finland, the frequency of the mutated allele was similar in the nondiabetic subjects and the subjects with NIDDM (12 vs. 11 percent). The mean age of the subjects at the onset of diabetes was lower among those with the mutation than those without it (56 vs. 61 years, P = 0.04). Among the nondiabetic subjects, those with the mutation had a higher ratio of waist to hip circumference (P = 0.02), a greater increase in the serum insulin response after the oral administration of glucose (P = 0.05), a higher diastolic blood pressure (82 vs. 78 mm Hg, P = 0.01), and a lower rate of glucose disposal during the clamp study (5.3 vs. 6.5 mg [29 vs. 36 mumol] per kilogram of body weight per minute; P = 0.04) than the subjects without the mutated allele. In an analysis of sibling pairs, the siblings with the mutation generally had higher waist:hip ratios (P = 0.05) and higher responses of blood glucose and serum insulin after the oral administration of glucose than their siblings without the mutation (P = 0.02 and P = 0.005, respectively). CONCLUSIONS: The Trp64Arg allele of the beta 3-adrenergic receptor is associated with abdominal obesity and resistance to insulin and may contribute to the early onset of NIDDM:

Age of Onset↗
PubMed1995

A rotator cuff rupture produces permanent osteoporosis in the affected extremity, but not in those with whom shoulder function has returned to normal.

Areal bone mineral density (BMD) and clinical status of 34 men treated surgically 9 years earlier for a rotator cuff rupture of the dominant side shoulder were determined. The BMD was measured at the lumbar spine (L2-L4) and the proximal humerus, humeral shaft, radial shaft, ulnar shaft, distal forearm, and hand of both extremities using a dual-energy X-ray absorptiometric (DXA) scanner. Thirty-four age-, height-, weight-, and profession-matched normal men (controls) were also measured. The patients' mean side-to-side BMD difference (dominant minus nondominant/nondominant x 100%) was significantly lower in the proximal humerus (patients -3.5% vs. controls +2.4%, p = 0.0002), humeral shaft (-2.6% vs. +1.6%, p = 0.0005), radial shaft (-0.4% vs. +1.9%, p = 0.0311), distal forearm (-0.2% vs. +2.4%, p = 0.0158), and hand (+2.3% vs. +4.0%, p = 0.0047). In the ulnar shaft, this difference was almost the same in the patients (-0.2%) and controls (+0.2%) (NS). Also, the lumbar spine BMD did not differ significantly between these groups (mean +/- SD = 1.098 +/- 0.148 g/cm2 in patients vs. 1.066 +/- 0.156 g/cm2 in controls). In patients, the relative BMDs of the injured extremity did not significantly associate with the size of the rupture; time delay between the injury and the surgery; type of surgery and postoperative treatment; postoperative immobilization time; follow-up time; patient's age, muscle strength or pain assessment; and subjective assessment of shoulder function. However, they strongly associated with the objective assessment of the shoulder function: the better the observed function of the shoulder, the less bone loss caused by the injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1995

Reconstruction of chronic anterior cruciate ligament insufficiency in athletes using a bone-patellar tendon-bone autograft. A two-year follow up study.

Thirty athletes (18 men and 12 women) were followed up for an average of 2.2 years after operative reconstruction for chronic anterior cruciate injuries with a mini-arthrotomy technique using a bone-patellar ligament-bone autograft. All the patients were active in sports, and the injuries in 40% occurred while playing soccer. The average delay between injury and reconstruction was 4.7 years; before this 26 knee operations had been carried out in 22 of the patients. At follow up, 20 patients were satisfied subjectively and 22 were classified objectively as excellent or good. Anteroposterior stability was good in 29 knees, and the Lachman and pivot shift tests were strongly positive in only one patient. Wasting of the thigh was more prominent in 9 patients who had a flexion deficit of 10 degrees or more, than in the other 21. Of the 15 competitive athletes, who had all given up their sport after injury, 8 were able to return to sport. Reconstruction using a bone-patellar ligament-bone autograft is recommended for symptomatic chronic anterior cruciate ligament insufficiency in athletes.

Anterior Cruciate Ligament↗
PubMed1995

Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity.

In muscle, hexokinase II (HK2) regulates phosphorylation of glucose to glucose 6-phosphate, which has been reported to be impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). Here we report decreased HK2 enzyme activity in skeletal muscle biopsies from patients with impaired glucose tolerance compared with healthy control subjects (2.7 +/- 0.9 vs 4.9 +/- 1.1 nmol.min-1.mg protein-1). Therefore, mutations in the HK2 gene could contribute to skeletal muscle insulin resistance in NIDDM. To address this question, we first determined the exon-intron structure of the human HK2 gene and using this information, we screened all 18 exons with single-strand conformation polymorphism technique in 80 Finnish NIDDM patients. Nine nucleotide substitutions were found, one of which was a missense mutation (Gln142-His142) in exon 4. In human muscle, a single HK2 mRNA transcript with a size of approximately 5500 nucleotides was detected with Northern blot analysis. We also describe an HK2 pseudogene (HK2P1), which was mapped to chromosome 4, band q26, by fluorescence in situ hybridization to metaphase chromosomes. The clinical characteristics and HK2 enzyme activities of the subjects with either Gln or His at residue 142 did not differ from each other. Instead, HK2 activity correlated inversely with fasting blood glucose levels, suggesting that changes in HK2 activity could be secondary to other metabolic abnormalities (r = 0.55; p < 0.0003; n = 39). In conclusion; the data suggest that impaired HK2 activity in prediabetic individuals is a consequence of impaired glucose tolerance rather than of a genetic abnormality. The data thus seem to rule out mutations in the HK2 gene as a major cause of inherited insulin resistance in NIDDM.

Aged↗
PubMed1995

Lack of association between the Gly40Ser polymorphism in the glucagon receptor gene and NIDDM in Finland.

A heterozygous polymorphism changing GGT40 (Gly) to AGT40 (Ser) (Gly40Ser) in the glucagon receptor gene was reported to be associated with non-insulin-dependent diabetes mellitus (NIDDM). A possible involvement of this polymorphism in impaired glucose tolerance was also suggested in a French population. To replicate this finding we screened 311 unrelated NIDDM patients, 101 unrelated individuals with impaired glucose tolerance and 306 control subjects for the presence of the Gly40Ser polymorphism by use of polymerase chain reaction-restriction fragment length polymorphism in a Finnish population. None of the NIDDM or impaired glucose tolerant patients had this polymorphism. Instead, four of the control subjects (1.3%) were heterozygous carriers of the polymorphism (NS). The age, body mass index, 2-h blood glucose level, 2-h insulin level, and incremental insulin are of the four subjects with this polymorphism were similar to those of the control subjects homozygous for the wild type. Taken together, the data do not support the suggested involvement of the Gly40Ser polymorphism in impaired glucose tolerance and the hypothesis of an association between NIDDM and the glucagon receptor gene in this population.

Alleles↗
PubMed1995

A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency--a clinical research center study.

Familial isolated GH deficiency type II (IGHD-II) is an autosomal dominant disorder that has been previously shown in some patients to be caused by heterogeneous GH gene defects that affect GH messenger RNA (mRNA) splicing. We report here our finding of multiple G-->A transitions of the first base of the donor splice site of IVS 3 (+ 1G-->A) in IGHD II subjects from three nonrelated kindreds from Sweden, North America, and South Africa. This + 1G-->A substitution creates an NlaIII site that was used to demonstrate that all affected individuals in all three families were heterozygous for the mutation. To determine the effect of this mutation on GH mRNA processing, HeLa cells were transfected with expression plasmids containing normal or mutant + 1G-->A alleles, and complementary DNAs from the resulting GH mRNAs were sequenced. The mutation was found to destroy the GH IVS 3 donor splice site, causing skipping of exon 3 and loss of the codons for amino acids 32-71 of the mature GH peptide from the mutant GH mRNA. Our finding of exon 3 skipping in transcripts of the + 1G-->A mutant allele is identical to our previous report of a different sixth base transition (+6T-->C) mutation of the IVS 3 donor splice site that also causes IGHD II. Microsatellite analysis of an affected subjects' DNA from each of the three nonrelated kindreds indicates that the + 1G-->A mutation arose independently in each family. Finding that neither grandparent has the mutation in the first family suggests that it arose de novo in that family. Our data indicate that 1) + 1G-->A IVS 3 mutations perturb GH mRNA splicing and cause IGHD II; and 2) these mutations can present as de novo GHD cases.

Adult↗
PubMed1994

Allergy to ingested cereals in atopic children.

Clinical features, hypersensitivity mechanisms, and differential diagnosis of cereal allergy or intolerance were investigated in children with atopic dermatitis (AD). On oral provocation, 18 children exhibited a positive response to wheat, three to rye, one to barley, and one to oats. Cereal-induced symptoms were dermatologic, gastrointestinal, or oropharyngeal, and their onset after provocation was immediate (eight cases), delayed (14 cases), or both immediate and delayed (one case). A combination of type I allergy tests (prick test, RAST, and histamine-release test) detected all immediate reactors and 9/14 delayed reactors. Of the five subjects remaining negative in these tests, three were positive in the patch or lymphocyte-proliferation tests. Subjects with cereal allergy or intolerance frequently possessed IgE, IgA, and IgG antibodies against gliadin, but only one of these children was HLA-DR3-positive, and none had reticulin antibodies typical of celiac disease. Combining tests of immediate and delayed hypersensitivity can confirm allergy to cereals in a more reliable way. The coexistence of cereal allergy and celiac disease seems to be rare.

Adolescent↗
PubMed1994

Comparison of immunologic tests in the diagnosis of occupational asthma and rhinitis.

In this study, three immunologic tests, skin prick test, RAST, and basophil histamine-release test (BHRT), were compared by provocation in the diagnosis of occupational asthma and rhinitis. Twenty-three positive bronchial or nasal challenges were performed on 16 patients (six farmers, six bakery workers, and four food industry workers) and asthma or rhinitis was diagnosed as caused by cereal flour or grain, cow epithelium, storage mites, garlic, or soy dust. A control group consisted of 12 patients, of whom four (two bakery workers, one food industry worker, and one farmer) were challenge-negative, and the rest suffered from pollen allergy and seasonal rhinitis and were not challenged. The sensitivity and specificity of the prick test, RAST, BHRT, and a panel of them were as follows: 74 and 89%, 57 and 86%, 78 and 93%, and 91 and 71%, respectively. The overall concordance among these three type I allergy tests or between immunologic tests and challenge was relatively good.

Adult↗
PubMed1994

Search for a third susceptibility gene for maturity-onset diabetes of the young. Studies with eleven candidate genes.

Maturity-onset diabetes of the young (MODY) is a model for genetic studies of non-insulin-dependent diabetes mellitus. We have identified 15 MODY families in which diabetes is not the result of mutations in the glucokinase gene. This cohort of families will be useful for identifying other diabetes-susceptibility genes. Nine other candidate genes potentially implicated in insulin secretion or insulin action have been tested for linkage with MODY in these families, including glucokinase regulatory protein, hexokinase II, insulin receptor substrate 1, fatty acid-binding protein 2, glucagon-like peptide-1 receptor, apolipoprotein C-II, glycogen synthase, adenosine deaminase (a marker for the MODY gene on chromosome 20), and phosphoenolpyruvate carboxykinase. None of these loci showed evidence for linkage with MODY, implying that mutations in these genes do not make a major genetic contribution to the development of MODY. In addition to these linkage analyses, one or two affected subjects from each family were screened for the presence of the A to G mutation at nucleotide 3,243 of the mitochondrial tRNA(Leu(UUR)) gene. This mutation was not found in any of these subjects. Finally, we report the localization of the gene encoding the regulatory protein of glucokinase to chromosome 2, band p22.3 and the identification of a restriction fragment length polymorphism at this locus.

Adolescent↗
PubMed1993

Mechanoreceptors in human myotendinous junction.

The sensory-nerve-ending system of 40 myotendinous junctions of human palmaris longus and plantaris muscles was studied histologically. All the known four types of nerve endings were identified. The Ruffini corpuscles could be found in equally small numbers (one to five) in both the muscular and tendineal sites of the junction. Also the free nerve endings were distributed equally on both sites. The Pacini corpuscles were frequent in the tendineal site (six to 14), but rare in the muscular site (one to three). The Golgi tendon organs were, in turn, frequent in the muscular site (nine to 12) but rare in the tendineal site (one to four), respectively. Within the muscle and tendon parts of the junction, the distance between two mechanoreceptors was always more than 250 microns and the receptor distribution was homogeneous. Further studies are needed to give functional explanation for these anatomic findings.

Adult↗
PubMed1993

Human hexokinase II: localization of the polymorphic gene to chromosome 2.

Type 2 (non-insulin-dependent) diabetes mellitus is characterized by decreased levels of glucose 6-phosphate in skeletal muscle. It has been suggested that the lower concentrations of glucose 6-phosphate contribute to the defect in glucose metabolism noted in muscle tissue of subjects with Type 2 diabetes or subjects at increased risk of developing Type 2 diabetes. Lower levels of glucose 6-phosphate could be due to a defect in glucose uptake, or phosphorylation, or both. Hexokinase II is the isozyme of hexokinase that is expressed in skeletal muscle and is responsible for catalysing the phosphorylation of glucose in this tissue. The recent demonstration that mutations in another member of this family of glucose phosphorylating enzymes, glucokinase, can lead to the development of Type 2 diabetes prompted us to begin to examine the possible role of hexokinase II in the development of this genetically heterogeneous disorder. As a first step, we have cloned the human hexokinase II gene (HK2) and mapped it to human chromosome 2, band p13.1, by fluorescence in situ hybridization to metaphase chromosomes. In addition, we have identified and characterized a simple tandem repeat DNA polymorphism in HK2 and used this DNA polymorphism to localize this gene within the genetic linkage map of chromosome 2.

Alleles↗