Genetic polymorphisms in peroxisome proliferator-activated receptor gamma are associated with Type 2 diabetes mellitus and obesity in the Korean population.

AIMS: We examined whether the common polymorphisms of the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene are associated with Type 2 diabetes or obesity in the Korean population. METHODS: We genotyped two common PPARgamma polymorphisms (Pro12Ala and 161C > T) and examined their association with the clinical phenotypes found in 684 patients with Type 2 diabetes mellitus and 291 non-diabetic control subjects. RESULTS: The 12Ala allele was less frequent in the Type 2 diabetic patients than in the non-diabetic control subjects (0.036 vs. 0.053, P = 0.024). The allele frequencies of the 161C > T polymorphism did not differ between the control and Type 2 diabetic group (0.158 vs. 0.173). In the non-diabetic controls, those with the T allele had lower BMI and fasting serum triglyceride (TG) concentrations than those with the C/C homozygote (22.7 +/- 2.9 vs. 23.8 +/- 3.2 kg/m2, P = 0.002; 1.45 +/- 0.81 vs. 1.65 +/- 0.83 mmol/l, P = 0.03, respectively). The 12Ala-161T haplotype was associated with a decreased risk for Type 2 diabetes (OR = 0.47, P = 0.009), whereas the 12Pro-161T haplotype was associated with lower BMI and lower fasting serum TG (22.5 +/- 2.8 vs. 23.7 +/- 3.2 kg/m2, P = 0.004; 1.41 +/- 0.87 vs. 1.64 +/- 0.79 mmol/l, P = 0.02, respectively). CONCLUSIONS: The PPARgamma 12Ala allele was associated with a reduced risk of Type 2 diabetes, whereas the PPARgamma 161T allele was associated with lower BMI and fasting serum TG concentrations in the Korean subjects. The subjects with 12Ala-161T haplotypes had a reduced risk of Type 2 diabetes.     

Predictors of insulin sensitivity in Type 2 diabetes mellitus.

AIMS: To identify the independent predictors of insulin sensitivity in Type 2 diabetes, and to establish whether isolated Type 2 diabetes (i.e. diabetes without overweight, dyslipidaemia and hypertension) is a condition of insulin resistance. METHODS: We examined 45 patients with non-insulin-treated Type 2 diabetes undergoing a 4-h euglycaemic hyperinsulinaemic clamp (20 mU/m2 per min) combined with 3H-3-D-glucose and 14C-U-glucose infusions and indirect calorimetry. We also examined 1366 patients with non-insulin-treated Type 2 diabetes randomly selected among those attending the Diabetes Clinic and in whom insulin resistance was estimated by Homeostasis Model Assessment (HOMA-IR). RESULTS: In the 45 patients undergoing glucose clamp studies, insulin-mediated total glucose disposal (TGD) was independently and negatively associated with systolic blood pressure (standardized beta coefficient = -0.407, P = 0.003), plasma triglycerides (beta= -0.355, P = 0.007), and HbA1c (beta= -0.350, P = 0.008). The overall variability of TGD explained by these variables was 53%. Overweight diabetic subjects with central fat distribution, hypertension, hypertriglyceridaemia and poor glycometabolic control had insulin-mediated TGD values markedly lower than their lean counterparts without hypertension, with normal triglycerides, and with good glycometabolic control (16 +/- 5 vs. 31 +/- 10 micromol/min per kg lean body mass, P < 0.01). Nevertheless, the latter still were markedly insulin-resistant when compared with sex- and age-matched non-diabetic control subjects (31 +/- 10 vs. 54 +/- 13 micromol/min per kg lean body mass, P < 0.01). In the 1366 Type 2 diabetic patients of the epidemiological study, HOMA-IR value was independently associated with HbA1c (beta = 0.283, P < 0.0001), plasma triglycerides (beta = 0.246, P < 0.0001), body mass index (beta = 0.139, P < 0.001), waist girth (beta = 0.124, P < 0.001) and hypertension (beta = 0.066, P = 0.006). CONCLUSION: Overweight, central fat distribution, dyslipidaemia, hypertension and poor glycometabolic control are strong independent predictors of insulin resistance in Type 2 diabetes. However, reduced insulin sensitivity can be found even when Type 2 diabetes is isolated and well controlled.     

Body composition in adolescent girls with type 1 diabetes.

AIMS: To compare body composition in adolescent girls with Type 1 diabetes with healthy controls. RESEARCH DESIGN AND METHODS: In this population-based study, body composition was examined, using dual-energy X-ray absorptiometry (DXA) and skinfold measurements, in 18 adolescent post-menarcheal females, 16-19 years of age, with Type 1 diabetes since childhood in comparison to age-matched healthy control subjects. RESULTS: Body mass index was 2.7 kg/m2 higher in diabetic patients (26.3 +/- 2.6 vs. 23.6 +/- 3.8; P < 0.05). The overweight consisted almost entirely of increased fat mass, as evaluated by both skinfold measurements and DXA. Bone mineral density did not differ between the two groups. In diabetic females, the distribution of the fat mass was increased in the upper part of the body. The fat distribution, expressed as the abdominal-to-leg ratio, was significantly correlated to glycated haemoglobin (HbA1c) (r = 0.69; P < 0.005), daily dosage of insulin expressed per kilogram body weight (r = 0.78; P < 0.0005) and total cholesterol (r = 0.60; P < 0.001). CONCLUSIONS: The observed overweight in adolescent females with Type 1 diabetes is explained by an increased fat mass. Abdominal fat accumulation was associated with poor glycaemic control, increased need for insulin and elevated blood lipids.     

A low-fat diet improves peripheral insulin sensitivity in patients with Type 1 diabetes.

AIMS: To compare the effects on insulin sensitivity, body composition and glycaemic control of the recommended standard weight-maintaining diabetes diet and an isocaloric low-fat diabetes diet during two, 3-month periods in patients with Type 1 diabetes. METHODS: Thirteen Type 1 patients were included, of whom 10 completed the cross-over study. Ten non-diabetic, matched control subjects were also examined. Body composition was estimated by dual-energy X-ray absorptiometry (DXA) whole-body scanning, diet intake was monitored by 7-day dietary record and insulin sensitivity was measured by the insulin clamp technique at baseline and after each of the diet intervention periods. RESULTS: On an isocaloric low-fat diet, Type 1 diabetic patients significantly reduced the proportion of fat in the total daily energy intake by 12.1% (or -3.6% of total energy) as compared with a conventional diabetes diet (P = 0.039). The daily protein and carbohydrate intake increased (+4.4% of total energy intake, P = 0.0049 and +2.5%, P = 0.34, respectively), while alcohol intake decreased (-3.2% of total energy intake, P = 0.02). There was a significant improvement in insulin sensitivity on the isocaloric, low-fat diet compared with the standard diabetes diet [7.06 +/- 2.16 mg/kg/min (mean +/- sd) vs. 5.52 +/- 2.35 mg/kg/min (P = 0.03)]. However, insulin sensitivity remained 33% lower than in the control subjects (P = 0.021). No significant changes occurred in body weight or body composition. Glycated haemoglobin rose during both diet intervention periods (P = 0.18), with no difference between the two diets. CONCLUSIONS: Change to an isocaloric, low-fat diet in Type 1 diabetic patients during a 3-month period resulted in significant improvement in insulin sensitivity without improvement in glycaemic control. However, insulin sensitivity remained 33% lower than in control subjects.     

Insulin resistance in type 2 diabetes: association with truncal obesity,impaired fitness,and atypical malonyl coenzyme A regulation

Abdominal obesity and physical inactivity are associated with insulin resistance in humans and contribute to the development of type 2 diabetes. Likewise, sustained increases in the concentration of malonyl coenzyme A (CoA), an inhibitor of fatty-acid oxidation, have been observed in muscle in association with insulin resistance and type 2 diabetes in various rodents. In the present study, we assessed whether these factors are present in a defined population of slightly overweight (body mass index, 26.2 kg/m2), insulin-resistant patients with type 2 diabetes. Thirteen type 2 diabetic men and 17 sex-, age-, and body mass index-matched control subjects were evaluated. Insulin sensitivity was assessed during a two-step euglycemic insulin clamp (infusion of 0.25 and 1.0 mU/kg x min). The rates of glucose administered during the low-dose insulin clamp were 2.0 +/- 0.2 vs. 0.7 +/- 0.2 mg/kg body weight x min (P < 0.001) in the control and diabetic subjects, respectively; rates during the high-dose insulin clamp were 8.3 +/- 0.7 vs. 4.6 +/- 0.4 mg/kg body weight x min (P < 0.001) for controls and diabetic subjects. The diabetic patients had a significantly lower maximal oxygen uptake than control subjects (29.4 +/- 1.0 vs. 33.4 +/- 1.4 ml/kg x min; P = 0.03) and a greater total body fat mass (3.7 kg), mainly due to an increase in truncal fat (16.5 +/- 0.9 vs. 13.1 +/- 0.9 kg; P = 0.02). The plasma concentration of free fatty acid and the rate of fatty acid oxidation during the clamps were both higher in the diabetic subjects than the control subjects (P = 0.002-0.007). In addition, during the high-dose insulin clamp, the increase in cytosolic citrate and malate in muscle, which parallels and regulates malonyl CoA levels, was significantly less in the diabetic patients (P < 0.05 vs. P < 0.001). Despite this, a similar increase in the concentration of malonyl CoA was observed in the two groups, suggesting an abnormality in malonyl CoA regulation in the diabetic subjects. In conclusion, the results confirm that insulin sensitivity is decreased in slightly overweight men with mild type 2 diabetes and that this correlates closely with an increase in truncal fat mass and a decrease in physical fitness. Whether the unexpectedly high levels of malonyl CoA in muscle, together with the diminished suppression of plasma free fatty acid, explains the insulin resistance of the diabetic patients during the clamp remains to be determined.     

Relationship between beta-cell responsiveness and fasting plasma glucose in Caucasian subjects with newly presenting type 2 diabetes.

AIMS : beta-cell responsiveness was related to fasting plasma glucose to gain further understanding of pathophysiology of Type 2 diabetes. METHODS : An insulin secretion model gave fasting beta-cell responsiveness M0 (ability of fasting glucose to stimulate beta-cell) and postprandial beta-cell responsiveness MI (ability of postprandial glucose to stimulate beta-cell) by analysing glucose and C-peptide time-concentration curves sampled every 10-30 min over 240 min during a meal tolerance test (MTT; 75 g CHO, 500 kcal). Caucasian subjects with newly presenting Type 2 diabetes according to WHO criteria (N = 83, male/female: 65 : 18, age: 54 +/- 10 years, body mass index (BMI): 30.9 +/- 5.2 kg/m2, fasting plasma glucose (FPG): 11.0 +/- 3.2 mmol/L; mean +/- SD) and Caucasian healthy subjects (N = 54, m/f: 21 : 33, age: 48 +/- 9 years, BMI: 26.1 +/- 3.7 kg/m2, FPG: 5.1 +/- 0.4 mmol/L) were studied. RESULTS : A continuum inverse relationship between MI and FPG was observed. In the diabetes group, MI was closely related to FPG (rs = -0.74, P < 0.0001) and explained 60% intersubject FPG variability with the use of an exponential regression model. CONCLUSIONS : In newly presenting Type 2 diabetes in Caucasian subjects a close inverse association exists between postprandial beta-cell responsiveness and FPG.     

Metabolic impact of a family history of Type 2 diabetes. Results from a European multicentre study (EGIR).

BACKGROUND: Insulin resistance was found in some but not in all previous studies of non-diabetic first degree relatives of Type 2 diabetic patients. Small study groups, ethnic differences and/or non-optimal techniques may explain the conflicting results. AIM: To study the impact of a family history of Type 2 diabetes on insulin action in a large group of non-diabetic Europeans using the 'gold standard' euglycaemic hyperinsulinaemic clamp technique. METHODS: Non-diabetic subjects (n = 235) with a positive family history of Type 2 diabetes (FH+) and 564 subjects with no family history of diabetes (FH-) were recruited from The European Group of Insulin Resistance (EGIR) database. This database includes measurements of insulin action using the insulin clamp technique (1 mU/kg per min) in normal glucose-tolerant individuals from 20 different European centres. In a subset of subjects the measurements were performed in combination with indirect calorimetry (n = 80 vs. 213 with and without family history of Type 2 diabetes). RESULTS: The body mass index (BMI) was slightly higher in FH+ compared with FH- (26.7 +/- 4.6 vs. 25.1 +/- 4.7 kg/m(2); P < 0.02). After correction for covariates according to differences between investigators and subject characteristics including BMI (multiple regression analysis), insulin-stimulated glucose disposal was lower in FH+ compared with FH- (P < 0.00001). Insulin-stimulated glucose oxidation was slightly increased in FH+ compared with FH-, and insulin-stimulated non-oxidative glucose metabolism was consequently markedly reduced in FH+ compared with FH- (P < 0.0005). CONCLUSION: Insulin resistance is present in European non-diabetic relatives of Type 2 diabetic patients. The insulin resistance is independent of degree of obesity and is restricted solely to the pathway of non-oxidative glucose metabolism. Diabet. Med. 18, 533-540 (2001)     

Less fat reduction per unit weight loss in type 2 diabetic compared with nondiabetic obese individuals completing a very-low-calorie diet program

The objective was to compare weight loss and change in body composition in obese subjects with and without type 2 diabetes mellitus during a very-low-calorie diet (VLCD) program. Seventy weight-matched subjects with diabetes or normal fasting glucose (controls) participated in a 24-week VLCD study. Primary end points were changes in anthropometry, body composition, and fasting plasma insulin and β-hydroxybutyrate concentrations. Fifty-one subjects (24 with diabetes) completed the study. No difference in weight loss between the 2 groups at 24 weeks was found by intention-to-treat analysis. Both groups completing the study per protocol had near-identical weight change during the program, with similar weight loss at 24 weeks (diabetes: 8.5 ± 1.3 kg vs control: 9.4 ± 1.2 kg, P = .64). Change in fat mass index correlated with change in body mass index (BMI) in both groups (diabetes: r = 0.878, control: r = 0.920, both P < .001); but change in fat mass index per unit change in BMI was less in the diabetic group compared with controls (0.574 vs 0.905 decrease, P = .003), which persisted after adjusting for age, sex, and baseline BMI (P = .008). Insulin concentrations remained higher and peak β-hydroxybutyrate concentrations were lower in the diabetic compared with the control group. While following a 24-week VLCD program, obese subjects with and without diabetes achieved comparable weight loss; but the decrease in adiposity per unit weight loss was attenuated in diabetic subjects. Hyperinsulinemia may have inhibited lipolysis in the diabetic group; however, further investigation into other factors is needed.     

Gastric bypass alters the dynamics and metabolic effects of insulin and proinsulin secretion.

AIMS: Hyperproinsulinaemia is associated with obesity and is a risk factor for Type 2 diabetes. We explored the dynamics of proinsulin and insulin and postprandial effects on glucose and lipids in subjects who had undergone gastric bypass (GBP) surgery compared with morbidly obese (MO) subjects and normal weight control subjects (NW). METHODS: Subjects free from diabetes were recruited: 10 previously MO subjects [body mass index (BMI) +/- sd, 34.8 +/- 6.2 kg/m2] who had undergone GBP surgery, 10 MO subjects (BMI 44 +/- 3.1 kg/m2) and 12 NW control subjects (BMI 23.2 +/- 2.4 kg/m2). After an overnight fast, a standard meal (2400 kJ) was ingested and glucose, proinsulin, insulin free fatty acids and triglycerides were determined up to 180 min. RESULTS: Fasting proinsulin was similar in the GBP group and NW control subjects, but threefold increased in MO subjects (P < 0.05). Postprandial AUC for glucose was similar in the three groups and AUC for proinsulin was high in MO, intermediate in the GBP group and lowest in NW control subjects (P for trend = 0.020). Postprandial proinsulin at 60 min was similar in the GBP group and MO subjects and twofold higher than in NW control subjects. Postprandial proinsulin at 180 min was normal in the GBP group, but fivefold increased in MO subjects (P = 0.008). Insulin increased rapidly at 30 min in the GBP group and was normal at 90 min, whereas insulin was still increased at 90-180 min in the MO subjects (P < 0.001). CONCLUSIONS: MO subjects, free from diabetes, have elevated proinsulin concentrations in the fasting as well as the postprandial phase. After GBP surgery markedly lower fasting and postprandial proinsulin concentrations were observed, although BMI was higher compared with NW control subjects.     

Effect of ageing and diabetes on glucose-dependent insulinotropic polypeptide and dipeptidyl peptidase IV responses to oral glucose.

AIMS: Glucose-dependent insulinotropic polypeptide (GIP) acts on the pancreas to potentiate glucose-induced insulin secretion (enteroinsular axis). GIP is rapidly inactivated in vivo by the enzyme dipeptidyl dipeptidase IV (DPP-IV). The current studies were designed to examine the effect of ageing, obesity and diabetes on GIP and DPP-IV responses to oral glucose. METHODS: Healthy controls (nine middle-aged, age 42 +/- 2 years, body mass index (BMI) 33 +/- 1 kg/m2; nine elderly, age 71 +/- 1 years, BMI 30 +/- 1 kg/m2) and patients with Type 2 diabetes (12 middle-aged, age 44 +/- 2 years, BMI 34 +/- 2 kg/m2; 19 elderly, age 74 +/- 1 years, BMI 31 +/- 1 kg/m2) underwent a 3-h oral glucose tolerance test (OGTT) (glucose dose 40 g/m2). RESULTS: Insulin responses were similar in elderly controls and patients with diabetes, but were lower in middle-aged patients with diabetes than in controls (308 +/- 65 vs. 640 +/- 109 pM, P < 0.05). GIP responses were similar in controls and patients with diabetes in each age group, but were higher in elderly controls (middle-aged 45 +/- 13; elderly 112 +/- 13 pM, P < 0.01) and patients with diabetes (middle-aged 55 +/- 10; elderly 99 +/- 10 pM, P < 0.01). DPP-IV levels were lower in patients with diabetes in both middle-aged (control 0.241 +/- 0.015; diabetes 0.179 +/- 0.017 delta OD/20 min, P < 0.05) and elderly groups (control 0.223 +/- 0.019; diabetes 0.173 +/- 0.010 delta OD/20 min, P < 0.05). CONCLUSIONS: It was concluded that ageing in obese subjects is associated with enhanced GIP responses to oral glucose. In addition, DPP-IV activity is reduced in middle-aged and elderly obese patients with diabetes.     

Association of the promoter polymorphism -232C/G of the phosphoenolpyruvate carboxykinase gene (PCK1) with Type 2 diabetes mellitus.

AIMS: The phosphoenolpyruvate carboxykinase gene (PCK1) is a potential candidate gene in the pathogenesis of Type 2 diabetes mellitus. A -232C/G promoter polymorphism of PCK1 has been associated with an increased risk of Type 2 diabetes in a Canadian population. The purpose of the present study was to examine this association in a German Caucasian population. METHODS: We investigated 397 subjects with Type 2 diabetes [227 men, 170 women, age 63 +/- 11 years, body mass index (BMI) 28.7 +/- 5.1 kg/m2] and 431 control subjects without diabetes (247 men, 184 women, age 64 +/- 7 years, BMI 26.5 +/- 3.7 kg/m2) matched for sex and age. RESULTS: In the diabetic and control groups, the CC genotype frequencies were 18.1 and 18.3%, the CG 48.6 and 48.7% and the GG 33.2 and 32.9%, respectively (P = 0.995). The allelic frequencies were 0.51 and 0.57 for the G allele and 0.49 and 0.43 for the C allele, respectively. In a logistic regression model only BMI and family history, but not the polymorphism, were predictors of Type 2 diabetes. In both the control and diabetic subjects, there were no significant differences in BMI or blood pressure between the groups with or without the polymorphism. The variant also had no significant influence on the presence of atherosclerotic disease, while the influence of other known cardiovascular risk factors was confirmed. CONCLUSIONS: The present data suggest that, in a German Caucasian population, the -232C/G polymorphism of the PEPCK gene is not associated with Type 2 diabetes.     

Effect of insulin treatment on the body composition of Type 2 diabetic patients.

OBJECTIVE: Insulin is used commonly in Type 2 diabetes and is often accompanied by weight gain. The composition of this weight gain is poorly understood. Predominant increases in fat mass could increase cardiovascular risks. The aim of the study was to evaluate insulin-induced body composition changes. RESEARCH DESIGN AND METHODS: Body weight and composition of 35 Type 2 diabetic patients during their first 6 months of insulin therapy was compared with those in 34 Type 2 diabetic individuals treated with insulin for at least 1 year prior to commencing the study. Body composition was determined by the simultaneous measurement of body water spaces and body density. RESULTS: Over 6 months, glycaemic control improved in the new treatment group only (HbA(1c): 7.26 +/- 0.81 vs. 9.66 +/- 1.60%; P < 0.0001), remaining stable in the previously treated group (7.67 +/- 1.25 vs. 7.76 +/- 1.26%; P = NS). Weight significantly increased over time in the newly treated group (+1.7 kg; P = 0.04), but not in the previously treated group (-0.3 kg). It comprised of both fat (+0.85 kg) and fat-free mass (+0.55 kg). Total body water remained unchanged. Using bioelectrical impedance analysis, the gain in fat mass was +2.2 kg; P = 0.048. CONCLUSIONS: Over 6 months, insulin therapy leads to a weight gain of 1.7 kg because of an increase in both fat and fat-free mass. When body composition is determined by bioelectrical impedance analysis, the results are biased by fluctuations in hydration.     

High prevalence and severity of cardiac autonomic neuropathy in Vietnamese diabetic patients.

AIMS: Malnutrition is frequent in Vietnamese people and may influence cardiac autonomic neuropathy (CAN). The aim of the present study was to investigate cardiac autonomic function in healthy subjects living in Vietnam and the prevalence of CAN in Vietnamese diabetic patients. METHODS: One hundred and five diabetic patients (BMI = 19.8 +/- 0.3 kg/m(2)), 50 Type 1 and 55 Type 2, living in Hué (Vietnam) were selected and compared with 60 non-diabetic healthy Vietnamese controls (BMI = 20.8 +/- 0.2 kg/m(2)) and also European controls. CAN function was evaluated by five standardized tests: three tests for heart rate variations (HRV) which depend mainly on parasympathetic activity, and two tests for blood pressure (BP) response which depend mainly on sympathetic activity. RESULTS: With age taken into account, 41 of the 60 Vietnamese controls had at least mild CAN, as defined by one abnormal test for HRV when compared with the European control series, and 11 of them had two or three abnormal tests. Among the Vietnamese control men, those with abnormal HRV had lower BMI than those without (P = 0.036). Seven Vietnamese controls had postural hypotension and 16 had an abnormal BP response to the handgrip test. Compared with the Vietnamese controls, 71 diabetic patients (67.6%), 40 Type 1 and 31 Type 2, had at least mild CAN, 37 of them had two or three abnormal HRV tests, and 56 diabetic patients (53.3%) had an abnormal BP response to the sympathetic tests. Abnormal HRV were associated with significantly lower BMI, waist and hip circumferences, longer diabetes duration and higher fasting blood glucose. In the logistic regression analyses, abnormal HRV were associated significantly with duration of diabetes and BMI in patients with Type 2 diabetes. CONCLUSIONS: Cardiac autonomic dysfunction is frequent in normal Vietnamese subjects. CAN appears to be a more frequent complication of diabetes in Vietnam than in Western countries and diabetic parasympathetic dysfunction is frequently associated with sympathetic disorders. This confirms the deleterious effect a poor nutritional state has on cardiac autonomic function.     

Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes.

AIMS: Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important insulinotropic hormones that enhance the insulin secretory response to feeding. Their potential for treating Type 2 diabetes is limited by short biological half-life owing to degradation by dipeptidyl peptidase IV (DPP IV). We investigated the acute effects of metformin on DPP IV activity in Type 2 diabetes to elucidate inhibition of DPP IV as a possible mechanism of action. METHODS: Eight fasting subjects with Type 2 diabetes (5M/3F, age 53.1+/-4.2 years, BMI 36.8+/-1.8 kg/m2, glucose 8.9+/-1.2 mmol/l, HbA1c 7.8+/-0.6%) received placebo or metformin 1 g orally 1 week apart in a random, crossover design. RESULTS: Following metformin, DPP IV activity was suppressed compared with placebo (AUC0-6 h 3230+/-373 vs. 5764+/-504 nmol ml/l, respectively, P=0.001). Circulating glucose, insulin and total GLP-1 were unchanged. Metformin also concentration-dependently inhibited endogenous DPP IV activity in vitro in plasma from Type 2 diabetic subjects. CONCLUSION: Oral metformin effectively inhibits DPP IV activity in Type 2 diabetic patients, suggesting that the drug may have potential for future combination therapy with incretin hormones.     

Two polymorphisms in the peroxisome proliferator-activated receptor-gamma gene are associated with severe overweight among obese women.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that regulates adipocyte differentiation. Variations in the PPARgamma gene may affect the function of the PPARgamma and, therefore, body adipocity. We investigated the frequencies of the Pro12Ala polymorphism in exon B and the silent CAC478CAT polymorphism in exon 6 of the PPARgamma gene and their effects on body weight, body composition, and energy expenditure in obese Finns. One hundred and seventy obese subjects [29 men and 141 women; body mass index (BMI), 35.7 +/- 3.8 kg/m2; age, 43 +/- 8 yr; mean +/- SD) participated in the study. The frequencies of the Ala12 allele in exon B and CAT478 allele in exon 6 were not significantly different between the obese and population-based control subjects (0.14 vs. 0.13 and 0.19 vs. 0.21, respectively). The polymorphisms were associated with increased BMI [Pro12Pro, 34.5 +/- 3.8; Pro12Ala, 34.8 +/- 3.1; Ala12Ala, 39.2 +/- 4.6 kg/m2 (P = 0.011); CAC478CAC, 34.5 +/- 3.8; CAC478CAT, 34.5 +/- 3.3; CAT478CAT, 37.7 +/- 4.1 kg/m2 (P = 0.046)]. In addition, the women with both Ala12Ala and CAT478CAT genotypes (n = 5) were significantly more obese compared with the women having both Pro12Pro and CAC478CAC genotypes (n = 85; BMI, 40.6 +/- 3.3 vs. 34.4 +/- 3.9 kg/m2; P = 0.001), and they had increased fat mass (46.8 +/- 9.1 vs. 36.8 +/- 7.5 kg; P = 0.005). In conclusion, the Pro12Ala and CAC478CAT polymorphisms in the PPARgamma gene are associated with severe overweight and increased fat mass among obese women.     

The innate immune response and type 2 diabetes: evidence that leptin is associated with a stress-related (acute-phase) reaction

OBJECTIVE: Leptin is produced by adipose tissue and controls food intake and body weight. Although blood levels of leptin reflect energy stores, cytokines also stimulate leptin production from fat. Because we have proposed that type 2 diabetes mellitus is associated with a cytokine-mediated acute-phase or stress response, part of the innate immune system, we sought evidence that leptin is increased in type 2 diabetes partly as a stress response, independently of obesity and sex. DESIGN: We selected two groups of type 2 diabetic patients with either a low acute-phase response (< 2.30 mmol/l serum concentration of the acute-phase marker sialic acid) or high response (> 2.30 mmol/l sialic acid), but pair-matched for body mass index (BMI) and sex. PATIENTS: Twenty type 2 diabetic subjects (11 male, 9 female) in each group, whose body mass index (BMI) and age were comparable (mean +/- SD: 28.8 +/- 3.8 vs. 28.9 +/- 3.8 kg/m2, and 60.7 +/- 8.9 vs. 61.9 +/- 12.3 years, low vs. high acute-phase responders, respectively). The glycaemic control was also similar in each group (glycated haemoglobin: 9.1 +/- 2.2 vs. 8.9 +/- 1.9%). MEASUREMENTS: Serum concentrations of sialic acid, leptin, interleukin-6 (IL-6) (the major cytokine mediator of the acute-phase response) and cortisol were assayed in fasting venous blood samples from patients and the results compared. RESULTS: Serum leptin concentration was increased in the high compared to the low acute-phase group (median 13.2 (range 3.6-55) vs. 8.1 (2.0-22.5) microg/l, P = 0.004). IL-6 and cortisol concentrations were also higher in the high-stress group (1.9 (1.0-6.4) vs. 1.4 (0.4-7.5) ng/l, P = 0.02; and 409 (180-875) vs. 290 (157-705) nmol/l, P = 0.02, respectively). Leptin was strongly correlated with BMI (r = 0.61, P < 0.001), but also with sialic acid (r = 0.40, P = 0.01) and IL-6 (r = 0.38, P = 0.04). CONCLUSIONS: Serum leptin concentrations in type 2 diabetes are partly related to an acute-phase or stress response, independent of BMI and sex. The association of hyperleptinaemia with elevated serum cortisol provides a mechanism for leptin resistance in type 2 diabetes (glucocorticoids inhibit the central action of leptin). This study provides further support for the theory that type 2 diabetes is asociated with chronic innate immune activation.     

Evidence of increased visceral obesity and reduced physical fitness in healthy insulin-resistant first-degree relatives of type 2 diabetic patients

OBJECTIVE: First-degree relatives (FDR) of type 2 diabetic patients are often insulin resistant. Visceral obesity is closely linked to both insulin resistance and type 2 diabetes. We therefore hypothesized that the inheritance of an increased tendency to store fat in visceral fat depots may be a characteristic phenotypic feature in FDR contributing to their insulin resistance. DESIGN AND METHODS: We measured fat distribution in 20 FDR and 14 age-, gender- and body mass index (BMI)-matched controls employing dual energy X-ray absorbtiometry (DEXA)- and computed tomography (CT)-scanning. Insulin-stimulated glucose uptake (ISGU) was determined by a hyperinsulinemic clamp and maximal aerobic work capacity (VO2 max) by a bicycle ergometer test. Baseline lipolysis was measured using [3H]palmitate. The activity level of the hypothalamic-pituitary-adrenal axis was assessed as the 24 h urinary (u)-cortisol/creatinine ratio. RESULTS: All subjects had a normal oral glucose tolerance test (OGTT), but FDR were insulin resistant (ISGU: 6.64+/-0.48 vs 9.12+/-0.98 mg/kg ffm/min, P=0.01). Despite similar BMI (25.2+/-0.5 vs 24.8+/-0.7 kg/m2, P=0.61) and overall fat mass (26.4+/-1.6 vs 24.2+/-2.1%, P=0.41) in FDR vs controls, the amount of visceral adipose tissue was substantially increased (65.9+/-10.0 vs 40.1+/-11.3 cm2, P<0.05) and VO2 max was reduced (52.2+/-3.1 vs 63.3+/-3.9 ml/kg ffm/min, P<0.05) in FDR. Visceral adiposity was inversely correlated with ISGU (FDR: r=-0.52, P<0.05; controls: r=-0.65, P<0.01) and in multiple regression analysis visceral adiposity (P<0.01), VO2 max (P<0.001) and a family history of type 2 diabetes (P<0.05) (r2=0.64) all significantly and independently contributed to the level of ISGU. Baseline palmitate appearance (145+/-10 vs 139+/-15 micromol/min, P=0.74) and the 24 h u-cortisol/creatinine ratio ((24.9+/-1.3 vs 27.4+/-2.0).10(-6), P=0.28) were both comparable in the two groups. CONCLUSION: Healthy but insulin-resistant FDR have enhanced visceral obesity and reduced VO2 max compared with people without a family history of diabetes, despite similar BMI and overall fat mass. Both the visceral adiposity and reduced aerobic fitness are strongly associated with and may contribute to their insulin resistance.     

The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes.

The aims of this study were to elucidate the factors that contribute to endothelial activation and fibrinolytic abnormalities in patients with poorly controlled type 2 diabetes and to determine whether improved glycemic control reduces endothelial activation. Adhesion molecules [E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1], von Willebrand factor, total nitric oxide (NO), endothelin-1, tissue plasminogen activator, and plasminogen activator inhibitor-1 were measured in 43 type 2 diabetic subjects with hemoglobin A1c of 9.0% or more at baseline (compared with 21 healthy controls) who after 20 wk had been randomized to either improved (IC) or usual (UC) glycemic control. At baseline, type 2 diabetic patients had significant endothelial activation and abnormal fibrinolysis compared with control subjects. Body mass index in the diabetic patients was the only independent predictor of E-selectin (P = 0.007), ICAM-1 (P = 0.01), and NO (P = 0.008) concentrations, but not vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, or tissue plasminogen activator (all P > 0.05). Type 2 diabetic patients with a body mass index of 28 kg/m2 or less had concentrations of E-selectin, ICAM-1, endothelin-1, and NO similar to those in healthy controls. After 20 wk, hemoglobin A1c was significantly lower in IC vs. UC (IC, 8.02 +/- 0.25%; UC, 10.23 +/- 0.23%; P < 0.0001), but there were no significant changes in markers of endothelial activation or indexes of fibrinolysis. Obesity appears to be the most important predictor of endothelial activation in patients with type 2 diabetes. Short-term improvement in glycemic control does not appear to reduce endothelial activation.     

Efficacy of continuous subcutaneous insulin infusion in Type 1 diabetes: a 2-year perspective using the established criteria for funding from a National Health Service.

AIM: To determine the 2-year efficacy of continuous subcutaneous insulin infusion (CSII) following the current established criteria for funding of a National Health Service. METHODS: Longitudinal, prospective, observational unicentre study. Included in the study were 153 Type 1 diabetes (T1D) subjects, previously treated with multiple daily injections (MDI) of insulin, in whom CSII was started in accordance with the criteria for reimbursement of the Catalan National Health Service. At baseline, we recorded data on age, gender, duration of the disease, body mass index (BMI), insulin dose and indications for CSII. Glycated haemoglobin (HbA(1c)) and the frequency of hypoglycaemic events were used to assess glycaemic control. Quality of life was assessed using three different self-report questionnaires. After 24 months, these same items were remeasured in all subjects. Serious adverse events and injection-site complications were also recorded. RESULTS: In 96% of subjects, CSII indication included less than optimal glycaemic control using MDI. HbA(1c) fell from 7.9 +/- 1.3 to 7.3 +/- 1.1% (P < or = 0.001) after 24 months of CSII. Insulin requirements were significantly lower at the end of follow-up (0.55 +/- 0.21 U/kg body weight) in comparison with before use of CSII (0.70 +/- 0.20, P < or = 0.001). BMI increased from 24.0 +/- 3.1 to 24.4 +/- 3.2 kg/m(2) after 24 months (P < or = 0.025). The rate of episodes of diabetic ketoacidosis per year remained unchanged. Mild and severe hypoglycaemic episodes were significantly reduced. The scores in all subsets of the Diabetes Quality-of-Life (DQoL) questionnaire significantly improved after 24 months of CSII. CONCLUSIONS: CSII, commenced according to the criteria for a nationally funded clinical programme, improves glycaemic control and quality-of-life outcomes with fewer hypoglycaemic episodes in T1D subjects previously conventionally treated with MDI.     

Elevated leptin levels are associated with excess gains in fat mass in girls, but not boys, with type 1 diabetes: longitudinal study during adolescence

Adolescents, in particular girls, with type 1 diabetes may gain excessive weight during puberty. We present the results of a longitudinal study aimed to determine the roles of leptin and insulin in changes in body composition in subjects with type 1 diabetes and controls. Forty-six children (23 boys) with type 1 diabetes and 40 controls (20 boys) were followed from 8-17 yr of age. Height, weight, and sc skinfolds were assessed every 6 months, and a blood sample taken for leptin determination. Throughout the age range, body mass index (mean +/- SEM) was greater by 1.45 +/- 0.69 kg/m(2) in girls and 1.46 +/- 0.55 kg/m(2) in boys with type 1 diabetes compared with control values. In girls with type 1 diabetes, this reflected greater percent body fat (3.2 +/- 1.0%; P = 0.002), whereas in boys it related to differences in fat-free mass. Both boys and girls with type 1 diabetes had higher leptin levels adjusted for percent body fat than controls; in the girls this was related to insulin dose (regression coefficient B = 0.006 +/- 0.003; P = 0.04) and greater gains in fat mass. Hyperinsulinemia and raised leptin levels are associated with gains in fat mass throughout puberty in girls, but not boys, with type 1 diabetes.