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An adipocyte-derived peptide, adiponectin (also known as GBP28), is decreased in subjects with type 2 diabetes. Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (APM1) is located. Herein, we present evidence of an association between frequent single nucleotide polymorphisms at positions 45 and 276 in the adiponectin gene and type 2 diabetes (P = 0.003 and P = 0.002, respectively). Subjects with the G/G genotype at position 45 or the G/G genotype at position 276 had a significantly increased risk of type 2 diabetes (odds ratio 1.70 [95% CI 1.09-2.65] and 2.16 [1.22-3.95], respectively) compared with those having the T/T genotype at positions 45 and 276, respectively. In addition, the subjects with the G/G genotype at position 276 had a higher insulin resistance index than those with the T/T genotype (1.61 +/- 0.05 vs. 1.19 +/- 0.12, P = 0.001). The G allele at position 276 was linearly associated with lower plasma adiponectin levels (G/G: 10.4 +/- 0.85 microg/ml, G/T: 13.7 +/- 0.87 microg/ml, T/T: 16.6 +/- 2.24 microg/ml, P = 0.01) in subjects with higher BMIs. Based on these findings together with the observation that adiponectin improves insulin sensitivity in animal models, we conclude that the adiponectin gene may be a susceptibility gene for type 2 diabetes.

It has been well demonstrated that insulin resistance plays an important role in the clustering of coronary risk factors through the progression of atherosclerosis in animal models of insulin resistance. In humans, a high-fat diet is the major cause of obesity and insulin resistance. In this study, we investigated the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in high-fat diet induced-obesity and insulin resistance by gene targeting and case-control study using the common PPARgamma2 polymorphism in human subjects. Homozygous PPARgamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet and the phenotypes were abrogated by PPARgamma agonist treatment. Heterozygous PPARgamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPARgamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARgamma. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARgamma, this polymorphism may be associated with decreased insulin resistance and decreased risk of Type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARgamma2 polymorphism. In an obese group, subjects with Ala12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against Type 2 diabetes. These results revealed that both in mice and humans, PPARgamma is a thrifty gene mediating Type 2 diabetes.

Diet treatment for diabetes requires restriction of the food amount (energy intake). It is desirable that patients have a proper relative consumption of the three main nutrients (proteins, carbohydrates, fats) and also habitually take low-energy foods such as vegetables, mushrooms and seaweeds, etc. as often as possible in each meal. Therefore, we can replace the expression 'a diet for diabetes' with 'a diet for healthy living'. By showing a clinical case of an obese diabetic patient, who succeeded to reduce their body weight, HbA1c and oral agents through diet treatment, and finally could go on diet treatment only, the importance of diet therapy can be emphasized. Furthermore, the estimation index was examined to evaluate how accurately diabetic patients could estimate food energy. According to this study, a large amount of food on the plate leads most patients to underestimate the amount of real energy, and patients are apt to eat too much compared with having smaller amounts of food on the plate. By analyzing questionnaires on the diet therapy of approximately 3000 diabetics, it has been shown that the majority of patients at our hospital recognize that diet therapy is the most important factor in the treatment of diabetes. Interestingly, patients who ate all the food served showed a significantly higher body mass index compared with those who left served food.

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been implicated in adipocyte differentiation. Recently it was reported that heterozygous deficiency of PPARgamma led to the protection from high-fat diet-induced insulin resistance in an animal model. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARgamma, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARgamma2 polymorphism in Japanese diabetic and non-diabetic subjects. The frequency of Ala12 was significantly lower in the diabetic group. In an overweight or obese group, subjects with Ala12 were more insulin sensitive than those without. These results suggest that the PPARgamma is a thrifty gene and that the Pro12Ala PPARgamma2 polymorphism protects against type 2 diabetes in the Japanese., (Copyright 2000 Academic Press.)

Diabetic nephropathy can be regarded mainly as a type of microangiopathy, but is a disease that may also include aspects of macroangiopathy. This is especially true of renal disease in non-insulin dependent diabetes mellitus (NIDDM), which is characterized not only by diabetic glomerulosclerosis, but also by atherosclerosis. We performed morphological studies on the kidney, using computed tomography (CT), focusing on such points as: (1) abdominal aortic calcifications at the level of kidney, (2) calcifications in the renal artery, and (3) wedge-shaped defects on the renal surface. We noted that these findings became more prominent in NIDDM patients during end-stage renal failure than during normal renal function, and were significantly more common in those two NIDDM groups than in age-matched nondiabetic patients without hypertension, hyperlipidemia or gout. NIDDM patients exhibited these features more frequently than IDDM patients.

The ATP-sensitive K channel (K-ATP channel) in pancreatic beta cells is believed to play a crucial role in glucose-stimulated insulin release. We investigated whether defects in the recently cloned gene for a putative subunit of this channel (KATP-2) could be a cause of diabetes in Japanese patients. The coding region of this beta-cell type channel gene was investigated in 192 diabetics with a family history of the disorder by single-stranded conformational polymorphism (SSCP) analysis. Two silent polymorphisms were found and confirmed by sequencing, but no missense or nonsense mutations were detected. The allele frequency of the polymorphisms was compared with 96 control subjects without a family history of the disease, and no clear difference was found. These results indicate that genetic defects of the KATP-2 channel may not be a major cause of diabetes in Japan.

The frequency of a positive family history of diabetes in diabetic patients has increased in recent studies. In this study, it was 16-33% for type 1 diabetes and 43-49% for type 2 diabetes. It was significantly higher than in non-diabetic subjects, and in type 2 than in type 1 diabetic patients. The prevalence of diabetes in parents and siblings of type 2 diabetic patients was higher than in those of type 1 patients, and it was particularly high in parents of young onset type 2 patients. Among type 2 diabetic patients, positive family history was somewhat lower in those with marked obesity in the past. Comparison of groups with varying degrees of glucose intolerance revealed that a family history of diabetes increased in parallel with the impairment of glucose tolerance. The results suggest that genetic factors in the pathogenesis of diabetes are more important in type 2 than in type 1 diabetes, and in the younger onset and less obese subjects than in older onset and more obese patients for type 2 diabetes.

Insulin (immunoreactive insulin, IRI) response during a 100 g oral glucose tolerance test was studied in a large number of patients with definite diabetes, equivocal diabetes, and other pathological states causing glucose intolerance. Definite diabetes was diagnosed in patients with overt fasting hyperglycemia. Once the diagnosis of definite diabetes was made, IRI response remained low after improvement of glucose tolerance. Glucose intolerance caused by other pathological extra-pancreatic conditions was usually accompanied by increased IRI response. IRI response in equivocal diabetes was variable, but almost always decreased in those who developed definite diabetes later. In subjects with a strong family history of type 2 diabetes, the prevalence of a low IRI response was high. In non-diabetic subjects, weight gain caused a marked increase in IRI response and a small increase in blood glucose, while in those who developed diabetes, IRI increased little despite the marked increase in blood glucose. These data suggest that low IRI response is an important feature of type 2 diabetes, perhaps with a hereditary basis in part. It precedes the occurrence of overt hyperglycemia and persists after improvement of glucose tolerance.

Risk factors for retardation of renal function in 22 patients with non-insulin-dependent diabetes mellitus (NIDDM) were studied and compared with those in 16 patients with insulin-dependent diabetes mellitus (IDDM). The annual decline rate of reciprocal serum creatinine was calculated from the rise of creatinine to the commencement of dialysis. The annual decline rate was compared with levels of blood pressure, fasting blood glucose, HbA1, and lipids, and clinical findings in patients with or without nephrotic syndrome during the same period. There was no significant difference in the rate of decline in levels of fasting blood glucose and HbA1, in IDDM and NIDDM. In NIDDM, the major risk factor is hypertension, as in IDDM. Triglycerides and total cholesterol also play roles in the retardation of renal function. Nephrotic syndrome also influenced the retardation of renal function in both IDDM and NIDDM.