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Objective: The phenotypic expression of partial lipodystrophy is present in two familial syndromes: familial partial lipodystrophy type 1 (FPLD1), with fat loss from the extremities, and central obesity and FPLD type 2, with fat loss from the extremities, abdomen, and thorax. The latter disorder is associated with mutations in the LMNA gene. FPLD1 is thought to be rare. Here, we report 13 subjects with FPLD1, suggesting that this syndrome is more common than previously thought., Research Design and Methods: Fasting glucose, plasma lipids, leptin, HbA(1c), and anthropomorphic measurements were evaluated in 13 subjects with clinical features of FPLD1 and are compared with two age-matched control groups, with and without diabetes., Results: Only women with clinical features of FPLD1 have been identified. Although they lack extremity and gluteal subcutaneous fat, they do have truncal obesity. Skinfold thickness on the arm and leg was significantly less than that in control subjects. The ratio of skinfold thickness from abdomen to thigh was significantly higher in subjects, suggesting an easy method for identifying affected patients. FPLD1 subjects also had components of the metabolic syndrome, including hypertension, insulin resistance, and severe hypertriglyceridemia resulting in pancreatitis. Premature coronary artery disease was present in 31% of subjects. None of the subjects had coding mutations in the LMNA gene or in the gene coding for peroxisome proliferator-activated receptor (PPAR)-gamma., Conclusions: FPLD1 is more common than previously described, but the diagnosis is often missed. Early recognition and intensive treatment of hyperlipidemia and diabetes in FPLD1 is important for prevention of pancreatitis and early cardiovascular disease.

Objective: To investigate the effect of the islet promoter region variant (G-->A) at nucleotide -30 of the glucokinase (GCK) gene on insulin levels in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and NIDDM., Research Design and Methods: The study population included 294 subjects with NGT, 83 subjects with IGT, and 36 subjects with NIDDM. Oral glucose tolerance tests (OGTTs) were performed in all subjects, and intravenous glucose tolerance tests (IVGTTs) were performed in subjects with NGT. The islet promoter region of the GCK gene was amplified with polymerase chain reaction and screened for the variant (-30) using single-strand conformation polymorphism analysis., Results: The islet promoter variant (-30) of the GCK gene was found in 17% of subjects with NGT, 23% of subjects with IGT, and 14% of patients with NIDDM (NS between the groups). Fasting, 1-h, and 2-h insulin levels, measured by OGTT, did not differ between subjects with and without this variant in any of the three groups. Furthermore, first-phase insulin secretion, determined by an IVGTT in subjects with NGT, did not associate with presence of the islet promoter region variant (-30) of the GCK gene., Conclusions: These results indicate that the variant (-30) of the islet promoter region of the GCK gene does not have a significant effect on insulin secretion in Finnish subjects with NGT, IGT, or NIDDM.

We sought to determine whether a G -> A variant at position -30 of the beta-cell promoter of the glucokinase (GCK) gene observed to be present more frequently in Japanese-American men with impaired glucose tolerance (IGT) than in Japanese-American men with normal glucose tolerance (NGT) is associated with impaired beta-cell function. We studied 125 unrelated Japanese-American men (aged 46-74 years; mean 61 +/- 0.5) who were nondiabetic by a 75-g oral glucose tolerance test (OGTT) (65 had NGT and 60 had IGT). The presence of the -30 beta-cell GCK gene promoter variant was determined by single-strand conformation polymorphism analysis. Beta-cell function was assessed using the ratio of the incremental response in immunoreactive insulin (IRI) to that of glucose during the first 30 min of the OGTT (delta IRI[30 min-0 min]/delta glucose[30 min-0 min]) performed at baseline and at 5 years of follow-up. Beta-cell function adjusted for basal IRI ([delta IRI[30 min-0 min]/delta glucose[30 min-0 min]]/basal IRI; the relative insulin response) was also evaluated. At baseline, the -30 beta-cell GCK gene promoter variant was present in 15.4% of subjects with NGT vs. 38.3% of subjects with IGT (P < 0.01). Fasting IRI did not differ between groups. At baseline, delta IRI[30 min-0 min]/delta glucose[30 min-0 min] was significantly lower in subjects with the promoter variant (57 x 10(-9) [35 x 10(-9) to 95 x 10(-9)] vs. 77 x 10(-9) [55 x 10(-9) to 128 x 10(-9)]; median [interquartile range]; P < 0.01) as was the relative insulin response (0.97 [0.70-1.24] vs. 1.37 [0.95-2.03]l/mmol; P < 0.0005). Similarly, at 5 years of follow-up, delta IRI[30 min-0 min]/delta glucose[30 min-0 min] and the relative insulin response were significantly reduced in the group with the variant. In the subgroups of subjects with IGT at baseline, IGT at 5 years, and NGT at 5 years, the relative insulin response was significantly lower in those with the variant. We conclude that the -30 beta-cell GCK gene promoter variant is associated with reduced beta-cell function in middle-aged Japanese-American men and may contribute to the high risk of abnormal glucose tolerance in this population.

Objective: To investigate the frequency of variants of the glucokinase (GCK) gene in subjects with late-onset non-insulin-dependent diabetes mellitus (NIDDM) and in subjects with late-onset impaired glucose tolerance (IGT)., Research Design and Methods: The study population included 36 Finnish patients with late-onset NIDDM who were treated with diet for > 8 years or who were newly diagnosed and 40 subjects with late-onset IGT who had low or normal insulin levels when tested by an oral glucose tolerance test. All exons, exon-intron junctions, and islet and liver promotor regions of the GCK gene were amplified with the polymerase chain reaction and screened for mutations using single-strand conformation polymorphism analysis., Results: A silent third-base substitution (TAC: >TAT) in codon 215 of exon 6 was found in 2.8% of NIDDM patients and in 5.0% of IGT subjects. Polymorphisms were found in islet exon 1 at nucleotide 403 (C-->G) in 16.7% of NIDDM patients and in 17.5% of IGT subjects and in the noncoding region of the islet promotor at nucleotide -30 (G-->A) in 13.9% of NIDDM patients and in 25.0% of IGT subjects. Furthermore, in liver intron 1 a variant (C-->T), 12 base pairs upstream from the splice acceptor site, was found in 5.6% of NIDDM patients and in 7.5% of IGT subjects., Conclusions: These results indicate that the mutations in the coding region of the GCK gene are not likely to play a major role the pathogenesis of late-onset NIDDM or IGT in the Finnish population.

Hexokinase (HK) II plays an important role in intracellular glucose metabolism by catalyzing the conversion of glucose to glucose-6-phosphate. HKII is considered to be a promising candidate gene for non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance. Therefore, we investigated the frequency of variants in the coding region of the HKII gene in patients with NIDDM. Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM, and subsequent screening included an additional 72 patients with NIDDM. By applying single-strand conformation polymorphism analysis and direct sequencing, the following amino acid substitutions were found among the 112 NIDDM patients: Ala314Val in one patient (0.9%), Arg353Cys in three patients (2.7%), and Arg775Gln substitution in three patients (2.7%). We also screened 97 subjects with completely normal glucose tolerance and a negative family history of diabetes for these mutations. The Ala314Val and the Arg353Cys substitutions were not found in control subjects, but the Arg775Gln substitution was found in two (2.1%) control subjects. None of these mutations were located close to the glucose- and ATP-binding sites of HKII. We conclude that mutations of the HKII gene are not a major etiological factor for NIDDM in the Finnish population.

Objective: To determine if sequence variants in the glucokinase (GCK) gene contribute to the high risk of impaired glucose metabolism in Japanese-Americans and whether the gene sequence differs between Japanese-Americans and Caucasians., Research Design and Methods: Forty-seven unrelated Japanese-Americans with one or more first-degree relatives with non-insulin-dependent diabetes mellitus (NIDDM) were selected, irrespective of glucose tolerance status. By World Health Organization criteria, 13 had normal glucose tolerance, 11 had impaired glucose tolerance, and 23 had NIDDM. Variations in the GCK gene were identified by single-strand conformation polymorphism analysis and sequenced using standard techniques., Results: Six variants of the GCK gene were identified in a total of 21 subjects: 1) a G--> A substitution at nucleotide -30 in the beta-cell-specific promoter; 2) an A--> G substitution at nucleotide 244 in the 5'-untranslated region (5'-UTR) of exon 1a; 3) a C--> G substitution at nucleotide 403 in the 5'-UTR of exon 1a; 4) a G--> A variant 13 base pair (bp) 5' to the intron 3 exon 4 junction; 5) a silent substitution in the third base of codon 145 in exon 4; and 6) a C--> T substitution 8 bp 3' to the exon 9 intron 9 junction. None of these variations would be expected to affect the structure of the GCK enzyme. While none of these variants were significantly associated with IGT or NIDDM, a nonsignificant increase in the beta-cell promoter variant was observed in subjects with abnormal glucose tolerance. No uniform sequence differences in the GCK gene were identified between Japanese-American and Caucasian-American subjects., Conclusions: Mutations affecting the amino acid sequence of GCK do not account for the increased incidence of impaired glucose metabolism in Japanese-Americans, and the gene sequence does not uniformly differ from that in Caucasians.