Obese Non-insulin-dependent Diabetes Mellitus Research Articles

The Crystal Structure of Carnitine Palmitoyltransferase 2 and Implications for Diabetes Treatment

Carnitine palmitoyltransferases 1 and 2 (CPTs) facilitate the import of long-chain fatty acids into mitochondria. Modulation of the catalytic activity of the CPT system is currently under investigation for the development of novel drugs against diabetes mellitus. We report here the 1.6 A resolution structure of the full-length mitochondrial membrane protein CPT-2. The structure of CPT-2 in complex with the generic CPT inhibitor ST1326 ([R]-N-[tetradecylcarbamoyl]-aminocarnitine), a substrate analog mimicking palmitoylcarnitine and currently in clinical trials for diabetes mellitus treatment, was solved at 2.5 A resolution. These structures of CPT-2 provide insight into the function of residues involved in substrate binding and determination of substrate specificity, thereby facilitating the rational design of antidiabetic drugs. We identify a sequence insertion found in CPT-2 that mediates membrane localization. Mapping of mutations described for CPT-2 deficiency, a hereditary disorder of lipid metabolism, implies effects on substrate recognition and structural integrity of CPT-2.

Effect of obesity and insulin on immunity in non-insulin-dependent diabetes mellitus.

To understand the effect of obesity and insulin on immune functions in non-insulin-dependent diabetes mellitus (NIDDM). Fourteen obese NIDDM (body mass index (BMI)=30.6+/-1.1), seven non-obese NIDDM (BMI=24.2+/-0.5) and five obese non-NIDDM (BMI=28.3+/-0.67). We first examined the influence of insulin on the proliferation of several human cell lines. Second, we compared several immune functions between obese and non-obese NIDDM, and obese non-NIDDM patients using peripheral blood mononuclear cells. Insulin decreased proliferation of T-cell lines but not that of other types of cell lines. Furthermore, obesity augmented the production of IL-1beta which could have cytotoxity against islet beta cells in NIDDM. Our data suggested that the pathophysiology of NIDDM could be affected by the change of immunity due to obesity, and the treatment of obesity in NIDDM may be important from an immunological aspect.

Vagal control of heart rate in obese non-insulin dependent diabetes mellitus patients

The aim of study was to analyse the vagal control of heart rate in non-insulin dependent diabetes mellitus (NIDDM) patients with different body mass. Age and gender matched NIDDM patients (men, 61±1.8 yr, Hb A1c 8.1±0.9%,) were divided in two groups according to the body mass index, with overweight (n=14; BMI>30 kg/m2) and without overweight (n=17; BMI<25 kg/m2). Beat-to-beat HR and finger mean arterial pressure were monitored noninvasively. The carotid baroreceptors were stimulated applying neck suction (-60 mm Hg, for 5s) 6 times at rest and with 15s intervals during handgrip for 60 s with force 50% of maximal voluntary contraction. HbA1c was significantly higher in obese patients (9.6±0.2 vs 7.7±0.6%; p<0.05). Finger mean arterial pressure was increased (109±2.9 vs 95±2.7 mm Hg; p<0.05), heart rate didn't differ significantly, but bradycardic reaction (1.2±0.6 vs 2.7±0.8 bpm; p<0.05) to baroreflex activation was reduced in NIDDM patients with overweight. The amplitude of pressor reaction (41±4 vs 30±2.6 mm Hg; p<0.05) was decreased in patients with overweight. Although heart rate (73±2.5 vs 78±3.3 bpm; NS) didn't differ significantly at rest in analysed groups, the amplitude of heart rate acceleration (23±2.7 vs 11 ±1.7 bpm; p<0.05) at 60th s of handgrip was decreased in obese patients and heart rate non-linear acceleration trajectory was altered, especially the rapid component of the curve during the first 10 s of exercise which is connected with reduction of cardiac vagal tone. The bradycardic reaction to baroreflex activation progressively decreased during whole static exercise in patients without overweight, but in obese patients it already disappeared in the first 15 s of handgrip. The present data show that vagal control of heart rate was altered in obese NIDDM patients, which probably is related with worse glycaemic control.

Genetic Dissection of “OLETF,” a Rat Model for Non-Insulin-Dependent Diabetes Mellitus: Quantitative Trait Locus Analysis of (OLETF × BN) × OLETF

To identify genetic determinants relevant to non-insulin-dependent diabetes mellitus (NIDDM), we performed a genome-wide analysis for quantitative trait loci (QTLs) using 359 backcross progeny of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF strain is a well-studied animal model of obese NIDDM, with features of hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. Our extensive genomic scanning with 218 markers revealed nine significant QTLs, including a strong determinant of obesity on chromosome 1 (Dmo1: LOD = 13.99, for body weight). Two highly significant QTLs for glucose homeostasis were found, one on chromosome 1 (Dmo4 LOD = 7.16, for postprandial glucose level) and the other on chromosome X (Dmo11/Odb1: LOD = 7.81, for postprandial glucose level). These data are comparable to results of our previous studies of the OLETF rat.

Dietary protein restriction alters glucose but not protein metabolism in non—insulin-dependent diabetes mellitus

We determine whether a customary diet high or low in protein (1) influences postabsorptive amino acid catabolism, nitrogen (N) balance, and hepatic glucose output (HGO) in normal subjects or patients with non—insulin-dependent diabetes mellitus (NIDDM) or (2) alters blood glucose levels in NIDDM. Eight normal young adults and five obese middle-aged persons with NIDDM consumed low-protein (0.8 g/kg lean body mass [LBM]) or high-protein (3.0 g/kg LBM) diets at maintenance energy for consecutive 7-day periods. Fasting and average blood glucose and N balance were measured daily. The level of dietary protein had no effect on the basal plasma leucine rate of appearance (Ra) or urinary 3-methylhistidine excretion in either subject group. Basal leucine oxidation (and by inference, whole-body amino acid catabolism) was reduced on the low-protein diet but basal HGO was not, and although exogenous glucose effectively suppressed HGO, it did not reduce leucine oxidation with either diet. After adaptation to the low-protin diet, N balance in both the normal and NIDDM subjects was close to zero. The low-protein diet reduced the fasting and daily blood glucose of the diabetic subjects by approximately 2 mmol/L ( P < .05). We conclude that physiologic variation in dietary protein does not affect basal whole-body protein turnover or HGD in either normal young adults or obese middle-aged NIDDM subjects. However, protein restriction to the level of the average daily requirement significantly reduces postabsorptive and average daily blood glucose concentrations in persons with NIDDM.

Serum levels of tumor necrosis factor-alpha are increased in obese patients with noninsulin-dependent diabetes mellitus.

To clarify the significance of the serum levels of tumor necrosis factor-alpha (TNF-alpha) in the mechanism of insulin resistance, we studied 12 obese patients with noninsulin-dependent diabetes mellitus (NIDDM). We evaluated the relationship of TNF-alpha levels with the visceral, subcutaneous, and total fat areas measured by computed tomography (CT), and with insulin resistance evaluated by the glucose infusion rate (GIR) observed during an euglycemic hyperinsulinemic clamp study. Controls consisted of 12 normal subjects and 12 nonobese patients with NIDDM. TNF-alpha levels were measured using a high sensitivity enzyme-linked immunosorbent assay. Following admission, all patients with NIDDM participated in a 4-week program of diet and exercise. After this treatment, we evaluated the relationship of the serum levels of TNF-alpha with the area of body fat, the GIR, and the resultant change in the TNF-alpha level. Serum levels of TNF-alpha in the obese patients with NIDDM significantly exceeded those observed in normal subjects (P < 0.01) or in the nonobese patients with NIDDM (P < 0.01). Serum levels of TNF-alpha in obese NIDDM patients showed a significant positive correlation with the area of visceral fat before (r = 0.662, P < 0.03) and after (r = 0.508, P < 0.05) the treatment; similar correlation was observed in all patients with NIDDM before (r = 0.537, P < 0.02) and after (r = 0.430, P < 0.05) the treatment. Serum levels of TNF-alpha in obese NIDDM patients showed a significant negative correlation with GIR after the treatment (r = -0.595, P < 0.05). Serum levels of TNF-alpha were significantly reduced in the obese patients with NIDDM after the treatment (P < 0.01), while those in the nonobese NIDDM patients were unchanged. These results suggest that serum TNF-alpha levels may play an important role in mechanism of insulin resistance associated with obesity.

Skeletal muscle peroxisome proliferator- activated receptor-gamma expression in obesity and non- insulin-dependent diabetes mellitus.

The two isoforms of peroxisome proliferator-activated receptor-gamma (PPARgamma1 and PPARgamma2), are ligand-activated transcription factors that are the intracellular targets of a new class of insulin sensitizing agents, the thiazolidinediones. The observation that thiazolidinediones enhance skeletal muscle insulin sensitivity in obesity and in patients with non-insulin-dependent diabetes mellitus (NIDDM), by activating PPARgamma, and possibly by inducing its expression, suggests that PPARgamma expression in skeletal muscle plays a key role in determining tissue sensitivity to insulin, and that PPARgamma expression may be decreased in insulin resistant subjects. We used a sensitive ribonuclease protection assay, that permits simultaneous measurement of the two isoforms, to examine the effects of obesity and NIDDM, and the effects of insulin, on skeletal muscle levels of PPARgamma1 and PPARgamma2 mRNA. We studied seven patients with NIDDM (body mass index, 32+/-1 kg/m2), seven lean (24+/-1 kg/m2), and six obese (36+/-1 kg/m2) normal subjects. Biopsies from the vastus lateralis muscle were taken before and after a 5-h hyperinsulinemic (80 mU/m2 per minute) euglycemic clamp. The obese controls and NIDDM patients were insulin resistant with glucose disposal rates during the last 30 min of the clamp that were 67 and 31%, respectively, of those found in the lean controls. PPARgamma1, but not PPARgamma2 mRNA was detected in skeletal muscle at 10-15% of the level found in adipose tissue. No difference was found in PPARgamma1 levels between the three groups, and there was no change in PPARgamma1 levels after 5 h of hyperinsulinemia. In obese subjects, PPARgamma1 correlated with clamp glucose disposal rates (r = 0.92, P < 0.01). In the lean and NIDDM patients, muscle PPARgamma1 levels correlated with percentage body fat (r = 0.76 and r = 0.82, respectively, both P < 0.05) but not with body mass index. (a) skeletal muscle PPARgamma1 expression does not differ between normal and diabetic subjects, and is not induced by short-term hyperinsulinemia; (b) skeletal muscle PPARgamma1 expression was higher in subjects whose percent body fat exceeded 25%, and this may be a compensatory phenomenon in an attempt to maintain normal insulin sensitivity.

Actions of the novel oral antidiabetic agent HQL-975 in genetically obese diabetic db/db mice.

The hypoglycemic effect of the novel oral agent 3-[4-12-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]-2S-propyla mino-propionic acid (HQL-975) was examined in db/db mice with genetically obese non-insulin dependent diabetes mellitus (NIDDM). The oral administration of HQL-975 at 3.5 and 35.3 mg/kg/d for 7 d decreased the plasma glucose level of these mice in a dose-dependent manner. HQL-975 also significantly decreased the plasma triglyceride, total cholesterol, non-esterified fatty acid and insulin levels. In the oral glucose tolerance test, HQL-975-treated mice showed improved glucose tolerance and decreased endogenous insulin secretion. HQL-975 increased glycemic response to exogenous insulin in the mice. In the HQL-975-treated db/db mice adipocytes, the glucose uptake, insulin binding, and GLUT4 expression were increased compared with those in untreated db/db mice adipocytes. These results indicate that HQL-975 improved insulin action in db/db mice through receptor and post-receptor effects. In conclusion, HQL-975 is a new oral antidiabetic agent with a hypoglycemic effect which is associated with an insulin-sensitizing effect. This agent may therefore be effective for the treatment of NIDDM.

Alterations of insulin and glucagon secretion from the perfused pancreas before, at the onset and after the development of diabetes in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an obese non-insulin dependent diabetes mellitus (NIDDM) model of an inbred strain. In this study, basal (2.8 mM glucose) insulin and glucagon and their responses to glucose (16.7 mM) were examined at the age of 9 weeks ( n=3) before the onset of diabetes, at 23 weeks ( n=6) at the onset of diabetes, and at 48 weeks ( n=5) after the development of diabetes by pancreatic perfusion. In Long-Evans Tokushima Otsuka (LETO, control) rats, insulin responses to glucose showed a biphasic pattern at all three ages, while in OLETF rats, basal insulin concentrations were significantly increased compared to those in controls at the age of 9 and 48 weeks. Insulin responses to glucose showed no difference from controls at 9 and 23 weeks, however, at 48 weeks the response was significantly decreased. In controls, high basal glucagon concentrations showed significant decrease in response to glucose at all ages. In OLETF rats, basal glucagon concentrations showed significant decrease compared to those in control rats at 23 and 48 weeks. Glucagon response to glucose significantly decreased at 9 and 23 weeks, but at 48 weeks there was no change in concentration in response to glucose. Pancreatic insulin content was lower at 48 weeks in OLETF rats than in LETO rats, although no differences were observed at other ages. There were no significant differences in pancreatic glucagon content between the two groups at any age. Morphologically, in OLETF rats the number of pancreatic B cells were decreased and A cells migrated into the center of islets at 48 weeks. The results suggested that one of the causes of diabetes in OLETF rats is impaired insulin response to glucose.

Insulin, the renin-angiotensin-aldosterone system and blood pressure.

INSULIN, THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND BLOOD PRESSURE JAMES F. TAIT and SYLVIA A. S. TAIT* There have been many studies of the possible correlation of insulin levels , e.g., blood insulin concentrations after overnight fasting or at various times after glucose loading, versus blood arterial blood pressure or the prevalence of hypertension. Subjects of different races with both normal and abnormal glucose tolerance, including patients with non-insulin dependent diabetes mellitus (NIDDM) have been studied. Role of Insulin in Determining Blood Pressure Considering all such reported studies, irrespective of the race of the subjects or whether the data are examined by uni- or multivariate analysis, the correlation between insulin levels and blood pressure is inconsistent [1, 2]. Multivariate analysis usually examines the confounding effects of variation in age, sex, and adiposity on the correlation of insulin levels and blood pressure. However, it has been shown that multivariate analysis involving interdependent variables, such as adiposity (e.g., BMI) and insulin levels, to form conclusions about the correlation of insulin level and blood pressure is ofdoubtful validity [3] . Also, there may be species and race variation in the strength of this correlation [4] . If data from Caucasians only are treated by univariate statistical analysis, then there is a more consistent correlation ofinsulin levels and blood pressure [5-11]. Univariate correlation in lean normotensive adult Caucasians was significant (P 40 years old) [55]. In Hisayama (Kyushu, southern Japan), also an area of relatively low salt intake , Ohmura, et al., found a highly significant correlation of insulin levels and blood pressures [56]. The corresponding results in Tokyo are more variable, possibly indicating differences in the birthplaces of the patients [57-59]. In general, present limited relevant data from Japan are not inconsistent with the predictions of the evolutionary theory concerning the 252 James F. Tait and Sylvia A. S. Tait ¦ Insulin and Blood Pressure inverse correlation ofinsulin-blood pressure and past salt intake. However, their quantity is inadequate for a critical assessment, and values for insulin levels are usually not given. Japanese, with normal glucose tolerance, show a positive correlation between blood pressure and salt intake [52; 53, p. 580] . These Japanese are not usually hyperinsulinemic. Therefore, it is not known whether the variation in insulin-blood pressure activities, as indicated in Japanese with NIDDM, may also be relatively important in determining the BP of normal Japanese. Conclusions on Differences in Insulin—Blood Pressure Activities The limited valid data presently available are not inconsistent with the evolutionary theory, which indicates that the present insulin-blood pressure activities of recently modernized hunter-gatherers are influenced by the environment of their ancestors, such as the conditions which determined their salt balance. However, until present insulin-blood pressure activities are determined by valid methodology and there is appropriate knowledge of the past environment, the theory cannot be rigorously tested. Nevertheless, present indications are that such investigations would be rewarding . Appendix: Correlation ofInsulin Level and Arterial Blood Pressure The results on die correlations of arterial blood pressure (mean [mBP] , systolic [sBP] or dBP [dBP] ) ? insulin blood levels (fasting [FI] and after glucose loading [RI] ) are from Meehan, et al., and also Zavaroni, et al., Pontremoli, et al., Berntorp, et al., Mykkanen, et al, Johnson, et al., and Schroll, et al. [5-11]. There were a total of 118 correlation studies from 42 reports (Table 1). The studies were divided according to the type of adult (>18 years), mainly Caucasian , subjects involved: (a) non-NIDDM, lean, normotensive; (b) non-NIDDM, obese, normotensive; and (c) early NIDDM. The studies were further divided as involving entirely or mainly males or females. However, in six studies there were equal numbers of male or females [60-62] . Other divisions were according to geographical situation (5 different European countries [63]) and age (18-, 21-, and 24year -olds [64] ) . To avoid bias, all divisions were initially maintained in the analysis. However, the results for FI and RI were pooled because the RI measurements were much smaller in number (about 25 percent) , and there was no difference statistically between the frequency of significant correlations for FI vs. BP compared with RI vs. BP. RESULTS The majority of studies (94 studies from 31 reports) were...

Genetic Analysis of Non-insulin-Dependent Diabetes Mellitus in the Otsuka Long–Evans Tokushima Fatty Rat

The Otsuka Long–Evans Tokushima Fatty (OLETF) rat is an animal model for obese NIDDM. We performed a genome wide scan in F2 progenies obtained by crossing OLETF rats with two control strains, Long–Evans Tokushima Otsuka (LETO) and Fisher-344(F-344) rats. Since diabetes develops only in male progenies, we used only male F2 rats for the linkage studies.Highly significant linkage was observed between the phenotype, postprandial hyperglycemia and P-450ald locus on chromosome 1 and D7Mit 11 locus on chromosome 7. In addition, suggestive linkage was found between fasting glucose level and body weight and these two loci. Four other regions (D1Mit12, D2Mit11, D5Mgh14, and D17Arb1) on chromosome 1, 2, 5, and 17 were detected to influence body weight, fasting glucose level or postprandial hyperglycemia independently. We concluded that non-insulin-dependent diabetes mellitus(NIDDM) in OLETF rats is regulated by multiple genes which affect fasting, postprandial hyperglycemia, and obesity differently.

Clinical profile of lean NIDDM in South India

The majority (>80%) of patients with non insulin dependent diabetes mellitus (NIDDM) present in Europe and America are obese. In developing countries like India, most NIDDM (>60%) are non-obese and many are actually lean with a body mass index (BMI) of <18.5 and are referred to as `lean NIDDM'. This paper compares the clinical profile of a cohort of 347 lean NIDDM, with a group of 6274 NIDDM of ideal body weight (IBW) and 3252 obese NIDDM attending a diabetes centre at Madras in South India. The lean NIDDM who constituted 3.5% of all NIDDM patients seen at our centre, had more severe diabetes and an increased prevalence of retinopathy (both background and proliferative), nephropathy and neuropathy. Although a larger percentage of the lean NIDDM patients were treated with insulin, 47% of the males and 53% of the females were still on oral hypoglycaemic agents even after a mean duration of diabetes of 9.2±8.1 years. Studies of GAD antibodies, islet cell antibodies (ICA) and fasting and stimulated C-peptide estimations done in a small subgroup of the lean NIDDM showed that they were distinct from IDDM patients. More studies are needed on metabolic, hormonal and immunological profile of lean NIDDM seen in developing countries like India.

Interaction between BTBR and C57BL/6J genomes produces an insulin resistance syndrome in (BTBR x C57BL/6J) F1 mice.

Insulin resistance is a common syndrome that often precedes the development of noninsulin-dependent diabetes mellitus (NIDDM). Both diet and genetic factors are associated with insulin resistance. BTBR and C57BL/6J (B6) mice have normal insulin responsiveness and normal fasting plasma insulin levels. However, a cross between these two strains yielded male offspring with severe insulin resistance. Surprisingly, on a basal diet (6.5% fat), the insulin resistance was not associated with fasting hyperinsulinemia. However, a 15% fat diet produced significant hyperinsulinemia in the male mice (twofold at 10 weeks; P < .05). At 10 weeks of age, visceral fat contributed approximately 4.3% of the total body weight in the males versus 1.8% in females. In the males, levels of plasma triacylglycerol and total cholesterol increased 40% and 30%, respectively, compared to females. Plasma free fatty acid concentrations were unchanged. Oral glucose tolerance tests revealed significant levels of hyperglycemia and hyperinsulinemia 15 to 90 minutes after oral glucose administration in the male mice. This was particularly dramatic in males on a 15% fat diet. Glucose transport was examined in skeletal muscles in (BTBR x B6)F1 mice. In the nonhyperinsulinemic animals (females), insulin stimulated 2-deoxyglucose transport 3.5-fold in the soleus and 2.8-fold in the extensor digitorum longus muscles. By contrast, glucose transport was not stimulated in the hyperinsulinemic male mice. Hypoxia stimulates glucose transport through an insulin-independent mechanism. This is known to involve the translocation of GLUT4 from an intracellular pool to the plasma membrane. In the insulin-resistant male mice, hypoxia induced glucose transport as effectively as it did in the insulin-responsive mice. Thus, defective glucose transport in the (BTBR x B6)F1 mice is specific for insulin-stimulated glucose transport. This is similar to what has been observed in muscles taken from obese NIDDM patients. These animals represent an excellent genetic model for studying insulin resistance and investigating the transition from insulin resistance in the absence of hyperinsulinemia to insulin resistance with hyperinsulinemia.

Pioglitazone-reduced insulin resistance in patient with Werner syndrome

Werner syndrome is a rare disorder that has provided a useful model for the study of human ageing. Patients with Werner syndrome usually display an aged appearance with various features including loss of hair, cataracts, atrophy of skin and peripheral fat, and diabetes. Mutations in the DNA helicase gene have been shown to be responsible for this disorder. One common feature of Werner syndrome is insulin resistance. However, as is the case in most patients with non-insulin-dependent diabetes mellitus (NIDDM), the precise mechanism underlying the disease is not known. As a step toward understanding the molecular mechanism of insulin resistance in Werner syndrome, we used pioglitazone, a new antidiabetic drug classified as a thiazolidinedione derivative, in a patient with Werner syndrome. Thiazolidinediones improve hyperglycaemia by enhancing insulin sensitivity without stimulating insulin secretion. These drugs have been shown to bind peroxisome proliferator-activated receptor (PPAR ), a dominant activator of fat-cell differentiation. This receptor is likely to mediate the antidiabetic effects of thiazolidinediones, since their affinity to PPAR correlates well with the strength of their effect as insulin sensitisers. A 53-year-old man with Werner syndrome was admitted for glycaemic control. The diagnosis was based on his clinical features and the reduced life-span of cultured fibroblasts. Although he was thin (body-mass index 14·2 kg/m) and had only a small amount of subcutaneous fat (%fat 4·9%), he had a moderate degree of insulin resistance as judged by the exogenous glucose infusion rate (GIR) during euglycaemic hyperinsulinaemic clamp (3·7 mg/kg per min, normal value 10·5 [SD 2·2]). His glycaemia was poorly controlled with a sulfonylurea agent, gliclazide. Written informed consent was obtained and the study was approved by the Institutional Ethical Committee. After 1 week of treatment by dietary restriction alone, pioglitazone 30 mg daily was initiated. After 12 weeks, the GIR had improved to 5·2 mg/kg per min (figure). This effect on the insulin sensitivity was similar to those observed in obese NIDDM patients; according to our data, the average GIR values for NIDDM patients (body-mass index 23 [SD 1·8]%, HbA1c 8·4 [1·4]%) before and after pioglitazone treatment was 8·2 [2·2] and 9·2 [2·0] mg/kg per min, respectively [p=0·003]; Kawamori R, Yamasaki Y, unpublished data). After 12 weeks of pioglitazone treatment, the patient’s fasting plasma glucose had decreased from 187 mg/dL (10·4 mmol/L) to 105 mg/dL (5·8 mmol/L) and glycated haemoglobin from 8·3% to 7·8%. All these glycaemic values deteriorated immediately after discontinuation of pioglitazone (figure). The fasting plasma insulin remained unchanged. These results suggest that pioglitazone was effective in ameliorating impaired insulin sensitivity and thus improved the glycaemic control in our patient. Recently, it was suggested that thiazolidinedione derivatives have direct effects on some tissues other than the adipose tissue, which has been considered to be the target organ of thiazolidinedione derivatives. Among the two isoforms of PPAR , PPAR 1, and PPAR 2, which can be activated to the same extent by a thiazolidinedione derivative, PPAR 1 (and maybe PPAR 2 also) seems to be weakly expressed in skeletal muscle. Also, a weak expression of PPAR 1 can be observed in liver, which seems to increase glucose uptake in response to pioglitazone. Thus, especially for this patient with Werner syndrome whose %fat was as low as 4·9%, the effects of pioglitazone on those non-adipose tissues may have had a role in improving the insulin sensitivity.

Lactate production by swine adipocytes: effects of age, nutritional status, glucose concentration, and insulin.

To develop an alternative model in which to study the relationship between adipose tissue lactate production, obesity, and non-insulin-dependent diabetes mellitus (NIDDM), we investigated lactate production by swine adipocytes. Subcutaneous adipocytes from fasted 3-wk-old, fasted 7-mo-old, and fed 7-mo-old Yucatan minIature swine were isolated and incubated with 0.2, 1, 5, 10, or 25 mM glucose +/- 1 mU/ml insulin. Total glucose metabolism (TGM) was estimated by product summation. Results showed that 1) TGM was threefold greater in cells from fasted 7-mo- vs. 3-wk-old swine (P < 0.05), 2) TGM was 2.7-fold greater in cells from fed 7-mo-old vs. fasted 7-mo-old swine (P < 0.05), 3) insulin failed to stimulate TGM in adipocytes from swine of either age and either nutritional status, and 4) lactate and pyruvate accounted for 34 and 30% of TGM, respectively, in adipocytes from swine of both ages. Similarities in glucose metabolism and lactate production in adipocytes from swine and obese NIDDM humans make the swine a potentially valuable model for studying lactate production associated with obesity and NIDDM.

Very low calorie diet (VLCD): A useful alternative in the treatment of the obese NIDDM patient

Conventional treatment of obese noninsulin dependent diabetes mellitus (NIDDM) patients is often unsatisfactory. In this study the efficacy of Modifast ®, a commercial very low calorie diet (VLCD), was evaluated in a population of obese poorly controlled NIDDM patients. The mechanisms of action of VLCD in these patients were also studied by comparing: (i) Plasma insulin and glucose profiles after a VLCD and an isocaloric mixed meal and (ii) plasma amino acid levels, both at baseline and after four weeks of VLCD treatment. A total of 14 obese NIDDM patients ( M F 7 7 , median body mass index (BMI) 38.7 kg −2, interquartile range (IQ) 34.7–46.5 kg −2, waist circumference 116 cm, IQ 106–139 cm, insulin treated 7 14 ) with poor diabetic control (HbA 1c 8.6%, IQ 7.8–10%) were studied. Patients were given a VLCD (425 kcal/day) for 12 weeks. At baseline, VLCD and isocaloric meal tests were performed on consecutive mornings. Fasting plasma amino acid levels were also determined at baseline and after 4 weeks of VLCD treatment. Weight, waist circumference, HbA 1c, blood pressure, fasting plasma insulin, total cholesterol and triglyceride levels all fell significantly following VLCD treatment. Insulin therapy was able to be ceased in the seven insulin treated patients. Oral hypoglycaemic agent dosage fell from a median of eight (IQ 6–12) to two (IQ 0–8) tablets per day ( P = 0.03) in patients initially on this form of therapy. Insulin secretion was higher after VLCD than isocaloric meal ( P = 0.04). Fasting plasma alanine level fell from 512.0 (IQ 412.0–563.0) to 374.0 (IQ 342–472.0) μmol/l ( P = 0.04) following VLCD treatment. In conclusion, the short term use of a VLCD is very effective in rapidly improving glycaemic control and promoting substantial weight loss in obese NIDDM patients. Moreover, a VLCD diet increases insulin secretion and reduces substrate for gluconeogenesis. Thus, VLCD treatment may improve glycaemic control by factors more than caloric restriction alone.

B-cell hyperresponsiveness to glucose in NIDDM during prediabetes.

It is not clear what is the initial metabolic abnormality in obese non-insulin-dependent diabetes mellitus (NIDDM). Recently established rat strain with naturally occurring obese NIDDM, Otsuka Long-Evans Tokushima Fatty (OLETF) rats,1 possesses remarkable resemblance to obese NIDDM in humans. Namely, the rats initially develop obesity, hyper-insulinemia, and glucose intolerance, and later, becomes hypoinsulinemic with diabetic renal pathology similar to end-stage renal lesion found in humans.1 Furthermore, development of glucose intolerance is virtually 100% in male OLETF,1 indicating the rats are useful for the delineation of initial metabolic abnormality in obese NIDDM. We examined 3 w-old (non-obese, euglycemic and normoinsulinemic) male OLETF rats in the present study, and found marked hyperresponsiveness of the B-cell to glucose in vitro.

Non‐insulin‐dependent Diabetes Mellitus (NIDDM) in Korea

The prevalence of diabetes mellitus in Korea has increased tremendously during the past several decades. In addition to the explosive increase of diabetes mellitus, the clinical characteristics of diabetes mellitus in Korea seems to be quite different from those of Western countries. Most patients with non-insulin-dependent diabetes mellitus (NIDDM) are non-obese and many of them lose weight significantly during the course of developing diabetes. The pathogenic mechanism(s) underlying this phenotype is still unclear. A subgroup of patients known as slow onset IDDM exists, but this could not explain the majority of non-obese NIDDM in Korea. In order to examine whether insulin resistance/hyperinsulinaemia is important in the development of NIDDM we conducted the following studies. Fasting plasma glucose and insulin concentration were measured in subjects with normal glucose tolerance, impaired glucose tolerance and diabetes mellitus. The peak plasma insulin level was much lower than that of Pima Indians or Caucasians. We also found that the insulin sensitivity index measured by euglycemic hyperinsulinaemic clamp in the first degree relatives of Korean NIDDM patients was not lower than that in a control group. This data suggests that insulin resistance, or hyperinsulinaemia, does not play a major role in the development of NIDDM in Korea. Taken together with the rarity of obese NIDDM in Korea, it maybe suggested that the insulin secretory capacity of Korean people being smaller than Western people they cannot compensate for the insulin resistance imposed by recent changes in life style.

Abnormalities of insulin pulsatility and glucose oscillations during meals in obese noninsulin-dependent diabetic patients: effects of weight reduction.

Twenty-seven obese patients, including 8 with normal glucose tolerance, 10 with subclinical NIDDM, and 9 with overt noninsulin-dependent diabetes mellitus (NIDDM), were studied before and after prolonged weight loss to assess the effects of the underlying defects of diabetes per se from those of obesity and chronic hyperglycemia on the regulation of pulsatile insulin secretion. Serial measurements of insulin secretion and plasma glucose were obtained during 3 standardized mixed meals consumed over 12 h. Insulin secretion rates were calculated by deconvoluting plasma C peptide levels using a mathematical model for C peptide clearance and kinetic parameters derived individually in each subject. Absolute (nadir to peak) and relative (fold increase above nadir) amplitudes of each insulin secretory pulse and glucose oscillation were calculated. Compared to the obese controls, the subclinical and overt NIDDM patients manifested the following abnormal responses: 1) decreased relative amplitudes of insulin pulses, 2) reduced frequency of glucose oscillations, 3) increased absolute amplitudes of glucose oscillations, 4) decreased temporal concomitance between peaks of insulin pulses and glucose oscillations, 5) reduced correlation between the relative amplitudes of glucose oscillations concomitant with insulin pulses, and 6) temporal disorganization of the insulin pulse profiles. These defects were more severe in the overt NIDDM patients, and weight loss only partially reversed these abnormalities in both NIDDM groups. These findings indicate that beta-cell responsiveness is reduced, and the regulation of insulin secretion is abnormal under physiological conditions in all patients with NIDDM, including those without clinical manifestations of the disease. These abnormalities are not completely normalized with weight loss, even in patients who achieve metabolic control comparable to that in obese controls. The results are consistent with the presence of an inherent beta-cell defect that contributes to secretory derangements in subclinical NIDDM patients. This abnormality precedes frank hyperglycemia and may ultimately contribute to the development of overt NIDDM.

Metformin: a new oral biguanide

The biguanide metformin is an oral anti-hyperglycemic agent used in the treatment of patients with non—insulin-dependent diabetes mellitus (NIDDM). Metformin is an important addition to the drug therapy options available for these patients because it reduces blood glucose levels predominantly by decreasing hepatic glucose production and release and also by increasing peripheral tissue sensitivity to insulin; it does not stimulate insulin secretion from the beta cells in the pancreas. Metformin also has a potentially beneficial effect by reducing serum lipid levels. Its glycemic control is similar to that of the sulfonylureas and is effective as monotherapy or in combination with sulfonylureas or insulin. Unlike sulfonylureas and insulin, it does not cause a gain in body weight, and when used as monotherapy, it does not cause hypoglycemia. The most common side effects associated with metformin are mild, transient, gastrointestinal symptoms, which are usually self-limiting. These side effects can be minimized by initiating metformin therapy at a low dose and gradually titrating upward, and by taking metformin with meals. Lactic acidosis caused by metformin is rare, and the risk of this complication may be diminished by the observance of prescribing precautions and contraindications that avoid accumulation of metformin or lactate in the body. In patients who are not getting the desired effect with sulfonylureas, it is useful to combine sulfonylureas with metformin therapy. Metformin should be considered a first-line agent, particularly in obese and/or hyperlipidemic NIDDM patients.