The relationships of glycemic control over time with the development of complications have been i... more The relationships of glycemic control over time with the development of complications have been investigated in several studies, but new areas of debate continue to arise. Does glycemic control have greater benefit when attained earlier than when attained later in the natural history of diabetes? Is it simply the duration of better or worse levels of glycemia that lead a given individual to have fewer or greater levels of complications? Might glycemic control have similar benefit throughout the duration of diabetes until irreversible damage occurs, perhaps varying by organ system (neurologic, renal, retinal, cardiovascular)? Specific benefits or adverse effects of treatment agents may further complicate the interpretation of what has been characterized as "metabolic memory." The notion of metabolic memory was based on findings of the Diabetes Control and Complications Trial (DCCT) of type 1 diabetes (T1D), in which the initial 2% HbA1c separation between the groups of pati...
Twenty-five patients (19 premenopausal women, 5 postmenopausal women, and 1 male) with advanced b... more Twenty-five patients (19 premenopausal women, 5 postmenopausal women, and 1 male) with advanced breast cancer were treated with a combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) at 3- to 4-week intervals. The median age of patients was 39 years (range 28-60). Twelve patients received treatment as first-line, and 13 as second-line, therapy. Of the 13 (52%) patients who responded, seven (28%) had complete response (CR). The median disease-free survival (DFS) was 6+ months. The response rate was highest for metastases in the pleura (80%), followed by liver (71%) and lymph nodes (62%). The overall response rate (83% versus 23%, p less than 0.01) was higher in previously untreated than in previously treated patients. Complete response rates of 50% and 8% and median DFS of 8.5+ months and 2 months, respectively, were observed in the two groups of patients. Severe anemia occurred more frequently in previously treated patients. The present study suggests a role for cisplat...
Lipodystrophies are heterogeneous disorders of adipose tissue, characterized by selective loss of... more Lipodystrophies are heterogeneous disorders of adipose tissue, characterized by selective loss of body fat and a predisposition to develop insulin resistance, diabetes mellitus, hyperlipidemia, and hepatic steatosis. These disorders can be either genetic or acquired. The extent of fat loss can also vary from being localized or partial to generalized. Among the genetic lipodystrophies, congenital generalized lipodystrophy is caused by mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli–Seip Congenital Lipodystrophy 2 (BSCL2) genes and familial partial lipodystrophies by defects in lamin A/C (LMNA) and peroxisome proliferator-activated receptor γ (PPARG) genes. Acquired generalized and partial lipodystrophies are likely to be autoimmune diseases. Lipodystrophy in HIV-infected patients is mainly due to prolonged treatment with HIV-1 protease inhibitors. Diabetes in patients with lipodystrophies may be caused by severe insulin resistance (hepatic and peripheral) and decrease in the insulin secretion due to pancreatic islet amyloidosis and β-cell atrophy. Hyperglycemia is difficult to manage despite large doses of insulin but does not lead to ketosis. Recombinant human leptin has been reported to drastically improve hyperglycemia and hypertriglyceridemia in lipodystrophy patients with low serum leptin levels. It is hoped that our understanding of the pathogenesis of these disorders will contribute to a better understanding of adipocyte physiology, and of the molecular mechanisms of insulin resistance and eventually to better therapeutic options. Keywords: lipodystrophy; adipose tissue; AGPAT (1-acylglycerol-3-phosphate O-acyltransferase); LMNA (lamin A/C); diabetes; hypertriglyceridemia; peroxisome proliferator-activated receptor-γ human immunodeficiency virus-1; protease inhibitors; hepatic steatosis; leptin
We describe clinical features, body fat distribution, and prevalence of metabolic abnormalities i... more We describe clinical features, body fat distribution, and prevalence of metabolic abnormalities in 35 patients with acquired partial lipodystrophy (APL) seen by us over 8 years, and also review 220 cases of APL described in the literature. Based on the review and our experience, we propose that the essential diagnostic criterion for APL is the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the "cephalocaudal" sequence, sparing the lower extremities. Analysis of the pooled data revealed that female patients were affected approximately 4 times more often than males. The median age of the onset of lipodystrophy was 7 years. Several autoimmune diseases, in particular systemic lupus erythematosus and dermatomyositis, were associated with APL. The prevalence rates of diabetes mellitus and impaired glucose tolerance were 6.7% and 8.9%, respectively. Approximately 83% of APL patients had low complement (C) 3 levels and the presence of polyclonal immunoglobulin C3 nephritic factor. Twenty-two percent of patients developed membranoproliferative glomerulonephritis (MPGN) after a median of approximately 8 years following the onset of lipodystrophy. Compared with patients without renal disease, those with MPGN had earlier age of onset of lipodystrophy (12.6 +/- 10.3 yr vs 7.7 +/- 4.4 yr, respectively; p < 0.001) and a higher prevalence of C3 hypocomplementemia (78% vs 95%, respectively; p = 0.02). The pathogenesis of fat loss and MPGN in patients with APL remains unclear, but activation of an alternate complement pathway has been implicated. Treating the cosmetic disfigurement by surgical procedures has yielded inconsistent results. The use of thiazolidinediones to treat fat loss in patients with APL remains anecdotal. Prognosis is mainly determined by renal insufficiency due to MPGN.
The prevention of diabetes was fi rst attempted in the 1960s, with phenformin and sulphonylureas.... more The prevention of diabetes was fi rst attempted in the 1960s, with phenformin and sulphonylureas. These early studies had design problems and were small. However, it was possible to obtain long-term follow-up data after the intervention was stopped, and such interventions, including antihyperglycaemic drugs, had some longterm benefi t. The 1990s saw several important studies in the prevention of diabetes. In most of these studies, a diet and exercise group was compared with drugs (metformin, acarbose, rosiglitazone, orlistat, etc). These trials were in individuals with prediabetes, had adequate samples and better design than previous studies, and follow-up of more than 4 years. The Diabetes Prevention Program (DPP), which included 3234 overweight middle-aged adults, was one of the largest and most rigorous trials, and compared placebo with an intensive lifestyle intervention and metformin. Overview of these studies showed that lifestyle management, including diet and exercise, led to a 31–58% risk reduction in the incidence of diabetes. Weight loss was the most important predictor of risk of diabetes. Indeed DPP data showed a 16% risk reduction for diabetes per kg of weight loss. Further, except for the thiazolidinediones (risk reduction 55–62%), risk reduction with other drugs was lower, ranging from 25% with acarbose up to 31% with metformin. Metformin was most eff ective in those with body-mass index above 35 kg/m2, in whom risk reduction was 50%. A study in Asian Indians showed that addition of metformin did not improve outcome in those who were already following intensive lifestyle management, although metformin was given in lower dose than in DPP. In the DPP trial, the eff ectiveness of intensive lifestyle intervention was similar across all ethnic groups, and was higher in those older than 60 years. Overall, results of all studies were remarkably similar: a carefully followed diet–exercise combination seemed to be superior in preventing or delaying the development of diabetes compared with the eff ect of antihyperglycaemic drugs other than the thiazolidinediones. In The Lancet today, the DPP Research Group reports the 10-year follow-up (DPPOS, the DPP outcomes study) of diabetes incidence and weight loss in 3150 individuals who entered the DPP. Group-administered lifestyle counselling, less rigorous and without behavioural therapy support than in DPP, was used in all three treatment groups after the fi ndings of DPP were opened. Despite poor attendance in these sessions, introduction of an intensive lifestyle intervention in the metformin and placebo groups might have been responsible for the absence of a signifi cant diff erence in the incidence of diabetes between the three groups. What does this study add? We now know from DPP and DPPOS that an intensive lifestyle intervention is eff ective over 10 years, and remains the best bet for prevention of diabetes. Further, during DPPOS, metformin did as well as an intensive lifestyle intervention, which might be due to addition of the lifestyle intervention to the drug group. Finally, some weight loss could be sustained over the 10 years of the lifestyle intervention and metformin, although during DPPOS, the loss of weight was not as impressive as that during DPP. Interestingly, elderly individuals attended lifestyle counselling sessions more often than did younger individuals, and the overall benefi t was also greatest in this group and was similar to that seen in DPP. DPPOS solves some but fails to answer other questions. As has been debated often, it is not clear whether metformin is masking, suppressing, or just delaying diabetes. Of particular interest is the statistically higher incidence of diabetes in the metformin group than in Published Online October 29, 2009 DOI:10.1016/S01406736(09)61631-7
We studied the impact of the multicomponent interventions on body weight and cardiometabolic risk... more We studied the impact of the multicomponent interventions on body weight and cardiometabolic risk factors in overweight individuals working in corporate worksites. Overweight (BMI ≥ 23 kg/m) subjects were recruited from four randomised worksites [two active intervention (, recruited, 180, completed 156) and two control (, recruited 130, completed 111)]. Intensive intervention was given at intervention worksite. High prevalence (%) of obesity (90.9, 80.2), abdominal obesity (93.5, 84.3), excess skinfold thickness (70.3, 75.9), and low high-density lipoprotein cholesterol (HDL-c) levels (56.8, 63.7) were seen in the intervention and the control group, respectively. At the end of intervention, the following significant changes were observed in the intervention group: decrease in weight, BMI, waist circumference, serum triglycerides, and increase in HDL-c. Weight loss of more than 5% was seen in 12% and 4% individuals in the intervention and control groups, respectively. Most importantl...
The relationships of glycemic control over time with the development of complications have been i... more The relationships of glycemic control over time with the development of complications have been investigated in several studies, but new areas of debate continue to arise. Does glycemic control have greater benefit when attained earlier than when attained later in the natural history of diabetes? Is it simply the duration of better or worse levels of glycemia that lead a given individual to have fewer or greater levels of complications? Might glycemic control have similar benefit throughout the duration of diabetes until irreversible damage occurs, perhaps varying by organ system (neurologic, renal, retinal, cardiovascular)? Specific benefits or adverse effects of treatment agents may further complicate the interpretation of what has been characterized as "metabolic memory." The notion of metabolic memory was based on findings of the Diabetes Control and Complications Trial (DCCT) of type 1 diabetes (T1D), in which the initial 2% HbA1c separation between the groups of pati...
Twenty-five patients (19 premenopausal women, 5 postmenopausal women, and 1 male) with advanced b... more Twenty-five patients (19 premenopausal women, 5 postmenopausal women, and 1 male) with advanced breast cancer were treated with a combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) at 3- to 4-week intervals. The median age of patients was 39 years (range 28-60). Twelve patients received treatment as first-line, and 13 as second-line, therapy. Of the 13 (52%) patients who responded, seven (28%) had complete response (CR). The median disease-free survival (DFS) was 6+ months. The response rate was highest for metastases in the pleura (80%), followed by liver (71%) and lymph nodes (62%). The overall response rate (83% versus 23%, p less than 0.01) was higher in previously untreated than in previously treated patients. Complete response rates of 50% and 8% and median DFS of 8.5+ months and 2 months, respectively, were observed in the two groups of patients. Severe anemia occurred more frequently in previously treated patients. The present study suggests a role for cisplat...
Lipodystrophies are heterogeneous disorders of adipose tissue, characterized by selective loss of... more Lipodystrophies are heterogeneous disorders of adipose tissue, characterized by selective loss of body fat and a predisposition to develop insulin resistance, diabetes mellitus, hyperlipidemia, and hepatic steatosis. These disorders can be either genetic or acquired. The extent of fat loss can also vary from being localized or partial to generalized. Among the genetic lipodystrophies, congenital generalized lipodystrophy is caused by mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli–Seip Congenital Lipodystrophy 2 (BSCL2) genes and familial partial lipodystrophies by defects in lamin A/C (LMNA) and peroxisome proliferator-activated receptor γ (PPARG) genes. Acquired generalized and partial lipodystrophies are likely to be autoimmune diseases. Lipodystrophy in HIV-infected patients is mainly due to prolonged treatment with HIV-1 protease inhibitors. Diabetes in patients with lipodystrophies may be caused by severe insulin resistance (hepatic and peripheral) and decrease in the insulin secretion due to pancreatic islet amyloidosis and β-cell atrophy. Hyperglycemia is difficult to manage despite large doses of insulin but does not lead to ketosis. Recombinant human leptin has been reported to drastically improve hyperglycemia and hypertriglyceridemia in lipodystrophy patients with low serum leptin levels. It is hoped that our understanding of the pathogenesis of these disorders will contribute to a better understanding of adipocyte physiology, and of the molecular mechanisms of insulin resistance and eventually to better therapeutic options. Keywords: lipodystrophy; adipose tissue; AGPAT (1-acylglycerol-3-phosphate O-acyltransferase); LMNA (lamin A/C); diabetes; hypertriglyceridemia; peroxisome proliferator-activated receptor-γ human immunodeficiency virus-1; protease inhibitors; hepatic steatosis; leptin
We describe clinical features, body fat distribution, and prevalence of metabolic abnormalities i... more We describe clinical features, body fat distribution, and prevalence of metabolic abnormalities in 35 patients with acquired partial lipodystrophy (APL) seen by us over 8 years, and also review 220 cases of APL described in the literature. Based on the review and our experience, we propose that the essential diagnostic criterion for APL is the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the "cephalocaudal" sequence, sparing the lower extremities. Analysis of the pooled data revealed that female patients were affected approximately 4 times more often than males. The median age of the onset of lipodystrophy was 7 years. Several autoimmune diseases, in particular systemic lupus erythematosus and dermatomyositis, were associated with APL. The prevalence rates of diabetes mellitus and impaired glucose tolerance were 6.7% and 8.9%, respectively. Approximately 83% of APL patients had low complement (C) 3 levels and the presence of polyclonal immunoglobulin C3 nephritic factor. Twenty-two percent of patients developed membranoproliferative glomerulonephritis (MPGN) after a median of approximately 8 years following the onset of lipodystrophy. Compared with patients without renal disease, those with MPGN had earlier age of onset of lipodystrophy (12.6 +/- 10.3 yr vs 7.7 +/- 4.4 yr, respectively; p < 0.001) and a higher prevalence of C3 hypocomplementemia (78% vs 95%, respectively; p = 0.02). The pathogenesis of fat loss and MPGN in patients with APL remains unclear, but activation of an alternate complement pathway has been implicated. Treating the cosmetic disfigurement by surgical procedures has yielded inconsistent results. The use of thiazolidinediones to treat fat loss in patients with APL remains anecdotal. Prognosis is mainly determined by renal insufficiency due to MPGN.
The prevention of diabetes was fi rst attempted in the 1960s, with phenformin and sulphonylureas.... more The prevention of diabetes was fi rst attempted in the 1960s, with phenformin and sulphonylureas. These early studies had design problems and were small. However, it was possible to obtain long-term follow-up data after the intervention was stopped, and such interventions, including antihyperglycaemic drugs, had some longterm benefi t. The 1990s saw several important studies in the prevention of diabetes. In most of these studies, a diet and exercise group was compared with drugs (metformin, acarbose, rosiglitazone, orlistat, etc). These trials were in individuals with prediabetes, had adequate samples and better design than previous studies, and follow-up of more than 4 years. The Diabetes Prevention Program (DPP), which included 3234 overweight middle-aged adults, was one of the largest and most rigorous trials, and compared placebo with an intensive lifestyle intervention and metformin. Overview of these studies showed that lifestyle management, including diet and exercise, led to a 31–58% risk reduction in the incidence of diabetes. Weight loss was the most important predictor of risk of diabetes. Indeed DPP data showed a 16% risk reduction for diabetes per kg of weight loss. Further, except for the thiazolidinediones (risk reduction 55–62%), risk reduction with other drugs was lower, ranging from 25% with acarbose up to 31% with metformin. Metformin was most eff ective in those with body-mass index above 35 kg/m2, in whom risk reduction was 50%. A study in Asian Indians showed that addition of metformin did not improve outcome in those who were already following intensive lifestyle management, although metformin was given in lower dose than in DPP. In the DPP trial, the eff ectiveness of intensive lifestyle intervention was similar across all ethnic groups, and was higher in those older than 60 years. Overall, results of all studies were remarkably similar: a carefully followed diet–exercise combination seemed to be superior in preventing or delaying the development of diabetes compared with the eff ect of antihyperglycaemic drugs other than the thiazolidinediones. In The Lancet today, the DPP Research Group reports the 10-year follow-up (DPPOS, the DPP outcomes study) of diabetes incidence and weight loss in 3150 individuals who entered the DPP. Group-administered lifestyle counselling, less rigorous and without behavioural therapy support than in DPP, was used in all three treatment groups after the fi ndings of DPP were opened. Despite poor attendance in these sessions, introduction of an intensive lifestyle intervention in the metformin and placebo groups might have been responsible for the absence of a signifi cant diff erence in the incidence of diabetes between the three groups. What does this study add? We now know from DPP and DPPOS that an intensive lifestyle intervention is eff ective over 10 years, and remains the best bet for prevention of diabetes. Further, during DPPOS, metformin did as well as an intensive lifestyle intervention, which might be due to addition of the lifestyle intervention to the drug group. Finally, some weight loss could be sustained over the 10 years of the lifestyle intervention and metformin, although during DPPOS, the loss of weight was not as impressive as that during DPP. Interestingly, elderly individuals attended lifestyle counselling sessions more often than did younger individuals, and the overall benefi t was also greatest in this group and was similar to that seen in DPP. DPPOS solves some but fails to answer other questions. As has been debated often, it is not clear whether metformin is masking, suppressing, or just delaying diabetes. Of particular interest is the statistically higher incidence of diabetes in the metformin group than in Published Online October 29, 2009 DOI:10.1016/S01406736(09)61631-7
We studied the impact of the multicomponent interventions on body weight and cardiometabolic risk... more We studied the impact of the multicomponent interventions on body weight and cardiometabolic risk factors in overweight individuals working in corporate worksites. Overweight (BMI ≥ 23 kg/m) subjects were recruited from four randomised worksites [two active intervention (, recruited, 180, completed 156) and two control (, recruited 130, completed 111)]. Intensive intervention was given at intervention worksite. High prevalence (%) of obesity (90.9, 80.2), abdominal obesity (93.5, 84.3), excess skinfold thickness (70.3, 75.9), and low high-density lipoprotein cholesterol (HDL-c) levels (56.8, 63.7) were seen in the intervention and the control group, respectively. At the end of intervention, the following significant changes were observed in the intervention group: decrease in weight, BMI, waist circumference, serum triglycerides, and increase in HDL-c. Weight loss of more than 5% was seen in 12% and 4% individuals in the intervention and control groups, respectively. Most importantl...
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