Pertti Mustajoki

Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome

Background:u2002 Mild hypoandrogenism in men, usually defined by low levels of testosterone, is a peculiar feature of abdominal obesity that independently predicts the development of insulin resistance and diabetes mellitus. Little is known about the short‐ and long‐term effects of weight loss on sex steroids in abdominally obese men, however.

Prognosis of Acute Prophyria: Occurrence of Acute Attacks, Precipitating Factors, and Associated Diseases

We evaluated the prognosis of acute porphyria among 206 adult Finnish patients with acute intermittent porphyria (AIP) or variegate porphyria (VP). The series represents all known patients with these porphyrias in Finland. Of the 47 patients who had a total of 117 acute attacks during the period 1967-1989, 6 died during an attack and 21 attacks were associated with paresis; the frequency of severe attacks was significantly smaller than before 1967 (p = 0.00002). Most pareses and deaths occurred because of a delay in diagnosis and inappropriate treatment of porphyria. For those patients who were symptom-free at the time of diagnosis (1365 follow-up years), the risk of the first subsequent attack was significantly smaller than for those who had had an acute attack before the diagnosis of porphyria (1047 follow-up years, p = 0.005). In addition, milder symptoms of porphyria were more common among those who had had previous attacks than among those who had not (p less than 0.00001). In AIP the risk of attacks correlated with the excretion of porphobilinogen in the urine during remission among adults (p = 0.03); a low rate of excretion predicted freedom from acute attacks. A regular use of many precipitating drugs was never associated with symptoms of porphyria. Two percent of the surgical operations and 4% of the pregnancies were associated with acute attacks. Nearly one-third of the women had symptoms of porphyria associated with the menstrual cycle, but these seldom proceeded to an acute attack. Forty-six percent of the women had used sex-hormone preparations regularly; 2 of them (4.5%) experienced associated acute attacks. Patients with AIP or VP showed increased incidences of hepatocellular carcinoma, and probably also chronic renal failure and hypertension.

The SLC6A14 gene shows evidence of association with obesity

In our previous genome-wide scan of Finnish nuclear families, obesity was linked to chromosome Xq24. Here we analyzed this 15-Mb region by genotyping 9 microsatellite markers and 36 single nucleotide polymorphisms (SNPs) for 11 positional and functional candidate genes in an extended sample of 218 obese Finnish sibling pairs (sibpairs) (BMI > 30 kg/m2). Evidence of linkage emerged mainly from the obese male sibpairs, suggesting a gender-specific effect for the underlying gene. By constructing haplotypes among the obese male sibpairs, we restricted the region from 15 Mb to 4 Mb, between markers DXS8088 and DXS8067. Regional functional candidate genes were tested for association in an initial sample of 117 cases and 182 controls. Significant evidence was observed for association for an SNP in the 3-untranslated region of the solute carrier family 6 member 14 (SLC6A14) gene (P = 0.0002) and for SNP haplotypes of the SLC6A14 gene (P = 0.0007-0.006). Furthermore, an independent replication study sample of 837 cases and 968 controls from Finland and Sweden also showed significant differences in allele frequencies between obese and non-obese individuals (P = 0.003). The SLC6A14 gene is an interesting novel candidate for obesity because it encodes an amino acid transporter, which potentially regulates tryptophan availability for serotonin synthesis and thus possibly affects appetite control.

Effect of Orlistat on Weight Regain and Cardiovascular Risk Factors Following a Very-Low-Energy Diet in Abdominally Obese Patients A 3-year randomized, placebo-controlled study

OBJECTIVE—To investigate the efficacy of orlistat on the maintenance of weight loss over 3 years following a major weight loss induced by very-low-energy diet (VLED) in obese patients with metabolic risk factors such as dyslipidemia, impaired fasting glucose, and diet-treated type 2 diabetes. RESEARCH DESIGN AND METHODS—Initially, weight loss was induced by an 8-week VLED (600–800 kcal/day) in 383 patients with a mean BMI of 37.5 kg/m2 (range 30.0–45.2). Those who lost ≥5% of their body weight (309 of 383 patients) were then randomized to receive lifestyle counseling for 3 years together with either orlistat 120 mg t.i.d. or matching placebo capsules. Primary end points were the maintenance of ≥5% weight loss after 3 years. Additionally, differences in the development of type 2 diabetes between orlistat and placebo were analyzed. RESULTS—The VLED induced a mean weight loss of 14.4 ± 2..0 kg among the subsequently randomized patients. The mean weight gain after 3 years was lower with orlistat than with placebo (4.6 ± 8.6 vs. 7.0 ± 7.1 kg; P < 0.02). The number of participants who achieved ≥5% weight loss also favored orlistat (67 vs. 56%; P = 0.037). Waist circumference was significantly more reduced in the orlistat group (P < 0.05), but no other differences in the risk factors were observed between the two groups. The incidences of new cases of type 2 diabetes were significantly reduced in the orlistat group (8 cases out of 153 subjects) versus placebo (17 cases out of 156 subjects) (P = 0.041). CONCLUSIONS—The addition of orlistat to lifestyle intervention was associated with maintenance of an extra 2.4 kg weight loss after VLED for up to 3 years in obese subjects. The combination of orlistat and lifestyle intervention was associated with a reduced occurrence of type 2 diabetes.

Health-related quality of life in obese outpatients losing weight with very-low-energy diet and behaviour modification: a 2-y follow-up study.

OBJECTIVE: To study health-related quality of life (HRQL) in a clinically selected sample of obese outpatients.DESIGN: A single-strand before and after study with 2-y follow-up after treatment comprising 10 weeks on very-low-energy diet (VLED) and 4 months of behaviour modification in groups.SUBJECTS: A total of 126 (mean (s.d.) age 48.2 (11.1)u2009y and body mass index 42.8 (6.2) kg/m2 obese patients (63% women) referred for treatment in an obesity clinic.MEASUREMENTS: Weight and HRQL using questionnaires (RAND 36-Item Health Survey 1.0 and Obesity-related Psychosocial problems scale (OP-scale)).RESULTS: A total of 100 patients (61% women) completed the treatment and 67 (71% women) completed the 2-y follow-up. The mean (s.d.) weight loss was 12.5 (5.6)% at the end of group therapy, 6.0 (7.1)% at 1u2009y, and 2.6 (7.5)% at 2u2009y. At baseline, the mean (s.d.) score for the OP-scale was 61.9 (24.6). The mean scores on every RAND-36 scale were markedly lower than in the Finns without chronic conditions. All the scales in HRQL improved markedly during the treatment. During the follow-up, all the scales started to return towards baseline levels, and at 2u2009y only obesity-related psychosocial problems and physical functioning were still improved relative to baseline. In categories of weight change at 2u2009y (≥10% weight loss, 0–9.9% weight loss, weight gain), obesity-related psychosocial functioning, physical functioning, and general health showed dose–response improvement with increasing weight loss. A ≥10% weight loss at 2u2009y after treatment was associated with clear improvement in obesity-related psychosocial problems, physical functioning, physical role functioning, bodily pain, general health, mental health, and vitality. A 0–9.9% weight loss was associated with improvement in obesity-related psychosocial problems and physical functioning. Weight gain was associated with improvement in obesity-related psychosocial problems and social functioning. The study population was too small to examine possible gender differences.CONCLUSIONS: Treatment with VLED and behaviour modification produces marked short-term weight loss and clear improvement in all aspects of HRQL. At 2u2009y after treatment, the average maintained weight loss is modest. However, 1/3 of patients maintained a ≥5% weight loss. Improvement in obesity-related psychosocial problems and physical functioning is associated even with less than 10% of maintained weight loss. Since the pattern of HRQL changes only partly followed the pattern of weight change as expected, other factors, such as the therapeutic effect of participating in the weight loss programme or increase in physical activity, may affect HRQL responses.

Comparison between repaglinide and glipizide in Type 2 diabetes mellitus: a 1‐year multicentre study

Aims To evaluate the long‐term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes.

Health-related quality of life in WHO Class II-III obese men losing weight with very-low-energy diet and behaviour modification: a randomised clinical trial

OBJECTIVE: To study health-related quality of life responses to marked weight loss in WHO Class II–III (body mass index (BMI) ≥35u2005kg/m2) obese men.DESIGN: An 8 month randomised clinical trial with a 4 month weight loss programme (10 weeks on a very-low-energy diet (VLED) and 17 behaviour modification visits) in the treatment group and no intervention in the control group.SUBJECTS: Nineteen men (mean age 45.9u2005y, mean BMI 39.3u2005kg/m2) in the treatment group and 19 men (47.2u2005y, 39.4u2005kg/m2) in the control group.MEASUREMENTS: Weight and questionnaires measuring health-related quality of life (RAND 36-Item Health Survey 1.0 and obesity-related psychosocial problems scale).RESULTS: In the treatment group, the mean (s.d.) weight loss was 17.0 (7.4)% at the end of the 4 month therapy. At the end of follow-up, nearly 6 months after the end of VLED in the treatment group, the average maintained weight loss was 13.9 (7.8)% of baseline weight. The control group was weight stable throughout the study. During treatment, there was only transient improvement in general health, bodily pain, mental health, emotional role functioning and vitality (all increases in the scores were not statistically significant). Improvements in physical functioning, social functioning and obesity-related psychosocial problems were maintained until the end of follow-up. The treatment group also reported improvement in perceived health in the past year. There was only minor fluctuation in questionnaire scores in the control group.CONCLUSION: The short-term and maintained health-related quality of life effects of weight loss may differ. Marked weight loss in WHO Class II–III obese men leads to improvements in physical functioning, social functioning, obesity-related psychosocial problems, and perceived health; these improvements were maintained at 4 month post-intervention follow-up.

Clinical and biochemical characteristics and genotype–phenotype correlation in Finnishvariegate porphyria patients

Variegate porphyria (VP) is an inherited metabolic disease resulting from the partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in the heme biosynthetic pathway. We have evaluated the clinical and biochemical outcome of 103 Finnish VP patients diagnosed between 1966 and 2001. Fifty-two per cent of patients had experienced clinical symptoms: 40% had photosensitivity, 27% acute attacks and 14% both manifestations. The proportion of patients with acute attacks has decreased dramatically from 38 to 14% in patients diagnosed before and after 1980, whereas the prevalence of skin symptoms had decreased only subtly from 45 to 34%. We have studied the correlation between PPOX genotype and clinical outcome of 90 patients with the three most common Finnish mutations I12T, R152C and 338G→C. The patients with the I12T mutation experienced no photosensitivity and acute attacks were rare (8%). Therefore, the occurrence of photosensitivity was lower in the I12T group compared to the R152C group (P=0.001), whereas no significant differences between the R152C and 338G→C groups could be observed. Biochemical abnormalities were significantly milder suggesting a milder form of the disease in patients with the I12T mutation. In all VP patients, normal excretion of protoporphyrin in faeces in adulthood predicted freedom from both skin symptoms and acute attacks. The most valuable test predicting an increased risk of symptoms was urinary coproporphyrin, but only a substantially increased excretion exceeding 1000u2009nmol/day was associated with an increased risk of both skin symptoms and acute attacks. All patients with an excretion of more than 1000u2009nmol/day experienced either skin symptoms, acute attacks, or both.

Acute intermittent porphyria: characterization of a novel mutation in the structural gene for porphobilinogen deaminase. Demonstration of noncatalytic enzyme intermediates stabilized by bound substrate.

To investigate the molecular pathology in acute intermittent porphyria (AIP), the nature of the defective porphobilinogen (PBG)-deaminase was determined in erythrocyte lysates from 165 AIP heterozygotes from 92 unrelated families representing 20 different ethnic or demographic groups. Immunologic and physicokinetic studies revealed the occurrence of four classes of PBG-deaminase mutations. In the majority of families studied, the amount of immunoreactive enzyme protein corresponded to the amount of enzymatic activity, indicating the absence of cross-reacting immunologic material (CRIM) produced by the mutant allele. In 78 of these CRIM-negative families (designated type 1), the affected heterozygotes had half-normal PBG-deaminase activity. In three families (designated CRIM-negative type 2), symptomatic patients had increased urinary excretion of delta-aminolevulinic acid and PBG, and normal levels of erythrocyte PBG-deaminase activity. In contrast, noncatalytic, immunoreactive protein was expressed in heterozygotes from 11 families, about one-eighth of those studied, consistent with mutations in the structural gene for PBG-deaminase. Two types of CRIM-positive mutations were identified: the type 1 mutation had a CRIM/activity ratio of approximately 1.7 and a crossed-immunoelectrophoretic profile in which all the enzyme intermediates were increased, with the B or monopyrrole-enzyme intermediate predominant (B greater than A much greater than C congruent to D greater than E). The mutation altered both the kinetic and stability properties of the noncatalytic immunoreactive enzyme protein. The second CRIM-positive mutation, type 2, had markedly increased levels of noncatalytic immunoreactive protein (CRIM/activity ratio approximately 5.7). Crossed-immunoelectrophoresis revealed markedly increased amounts of the substrate-bound intermediates, B, C, D, and E (B greater than C greater than D greater than E much greater than A). The accumulation of these noncatalytic enzyme intermediates presumably resulted from the enhanced binding and/or defective release of substrate molecules. The conformation of these enzyme-substrate intermediates apparently rendered the complexes more resistant to intraerythrocyte proteolysis. These findings provide evidence for the presence of different allelic mutations in the structural gene for PBG-deaminase and document molecular genetic heterogeneity in AIP.

Novel polymorphism of the human ob gene promoter in lean and morbidly obese subjects

OBJECTIVE: Leptin, the circulating product of the human ob gene, may play role in control of appetite and metabolic rate. We screened the proximal promoter area of the ob gene for mutations and common polymorphisms in order to find out whether genetic variation in the regulatory area of this gene plays a role in human obesity. DESIGN: The technique of single‐strand‐conformation polymorphism (SSCP) was applied to screen for the promoter area of the ob gene for genetic alterations in morbidly obese patients. SUBJECTS: A total of 249 morbidity obese (present or past body mass index [BMI;[ge;40u2005kg/m2) and 141 lean (BMI≤25u2005kg/m2) subjects. MEASUREMENTS: DNA analysis was carried out using a single-strand conformation polymorphism (SSCP) technique and PCR followed by digestion with the restriction enzyme BssHII. Leptin was determined by radioimmunoassay in obese subjects. Serum lipids, glucose and insulin concentrations in the obese subjects were also determined. RESULTS: A new polymorphism C(-188)A was identified in the promoter region of the ob gene. This polymorphism was detected with allelic frequencies of 0.06 in morbidly obese subjects and 0.09 in lean controls (P=0.28). Initial studies failed to show an association of this polymorphism with serum leptin, response to treatment for obesity, history and extent of weight gain, or serum insulin, glucose of lipid concentrations. CONCLUSIONS: We have identified a common polymorphism in the promoter area of the human ob gene which appears to be very useful for genetic association and linkage studies. Further studies are needed to elucidate its potential role in the regulation of the human ob gene and in human metabolic disorders.