patients with t2 dm and pll were identified by one of the authors ( w.t.g . ) in clinics sponsored by divisions of endocrinology or nutrition sciences at academic institutions during a 25-year period .
ten of these patients ( half of the total ) agreed to participate in metabolic studies on a research ward and constitute the current study population .
all patients with pll in the study were females of various ethnic and racial identities .
there are no reasons to suspect men can not also be affected by t2 dm and pll , even though men may be more difficult to identify than women because of differences in subcutaneous fat .
in fact , we encountered one such hispanic man with symmetrical lipoatrophy of the forearms who did not agree to participate in this study .
nine of the patients with pll in the study had overt t2 dm , whereas one met the criteria for prediabetes .
five of the nine pll patients with t2 dm were treated with insulin plus metformin or a sulfonylurea and the remainder with oral hypoglycemic drugs .
a single laboratory conducted the metabolic studies , assuring continuity of methods and comparability of data during this interval . characteristics of patients with t2 dm with pll compared with patients with common t2 dm from a larger database of t2 dm patients metabolically studied in the same laboratory , the patients with pll were matched by age , bmi , fasting glucose , ethnicity , and diabetes status to 10 patients with commonly occurring t2 dm who did not have clinically evident lipodystrophy .
comparative data in the study groups with and without pll are also delineated in table 1 .
all patients were withdrawn from any medicines used to treat diabetes or dyslipidemia for 1 to 3 weeks so that they could be studied in the untreated state .
all patients denied positivity for hiv and explicitly denied that any other family members had the appearance or diagnosis of lipodystrophy to their knowledge .
none of the patients engaged in heavy alcohol use ( more than 2 drinks / day or 10 drinks / week ) , and orthostatic hypotension was excluded by sitting and standing blood pressure checks .
this study was approved by the institutional review boards of the institutions , and written informed consent was obtained in all patients .
patients were equilibrated on a metabolic ward on a diet consisting of 20% protein , 30% fat , and 50% carbohydrate for 3 days .
standard 75-g oral glucose tolerance tests were performed after an overnight fast . to assess glucose disposal rates ( gdrs ) ,
hyperinsulinemic - euglycemic clamps were performed at a maximally effective insulin concentration , as previously described ( 19 ) .
a catheter was inserted into the brachial vein , and a calibrated syringe pump was used to administer regular insulin in a square wave at a rate of 200 mu / m / min .
this infusion provided steady - state serum insulin levels that were maximally effective for promoting glucose uptake in skeletal muscle in patients with t2 dm and fully suppressing hepatic glucose production ( 19 ) . to prevent hypokalemia ,
a variable - rate infusion of a 20% dextrose solution was used to maintain the plasma glucose level at 90 mg / dl for at least 3 h , with plasma glucose levels assessed every 5 min throughout the clamp . during the final three 20-min intervals , the mean glucose infusion rate was used to calculate maximal glucose uptake for each individual . whole - body glucose uptake was calculated based on the glucose infusion rate corrected for changes in the glucose pool size , assuming a distribution volume of 19% body weight and a pool fraction of 0.65 . under these conditions ,
the glucose infusion rate in milligrams per minute is equal to the gdr , and the data were normalized to total body weight ( kg ) or body surface area ( m ) .
if normally distributed , the data were expressed as mean  se , and the student t test was used to analyze whether differences between the patients with t2 dm with and without pll were statistically significant .
if data were not normally distributed , values were presented as median ( first  third quartile ) , and statistical significance was determined using the nonparametric wilcoxon rank test .
statistical analysis was performed using sas 9.2 software ( sas institute , cary , nc ) and microsoft excel .
serum alanine aminotransaminase ( alt ) , aspartate aminotransaminase ( ast ) , and alkaline phosphatase ( alp ) values were expressed as a percentage of the clinical laboratory s established upper limit of the normal reference range .
patients with t2 dm and pll were identified by one of the authors ( w.t.g . ) in clinics sponsored by divisions of endocrinology or nutrition sciences at academic institutions during a 25-year period .
ten of these patients ( half of the total ) agreed to participate in metabolic studies on a research ward and constitute the current study population .
all patients with pll in the study were females of various ethnic and racial identities .
there are no reasons to suspect men can not also be affected by t2 dm and pll , even though men may be more difficult to identify than women because of differences in subcutaneous fat .
in fact , we encountered one such hispanic man with symmetrical lipoatrophy of the forearms who did not agree to participate in this study .
nine of the patients with pll in the study had overt t2 dm , whereas one met the criteria for prediabetes .
five of the nine pll patients with t2 dm were treated with insulin plus metformin or a sulfonylurea and the remainder with oral hypoglycemic drugs .
a single laboratory conducted the metabolic studies , assuring continuity of methods and comparability of data during this interval . characteristics of patients with t2 dm with pll compared with patients with common t2 dm from a larger database of t2 dm patients metabolically studied in the same laboratory , the patients with pll were matched by age , bmi , fasting glucose , ethnicity , and diabetes status to 10 patients with commonly occurring t2 dm who did not have clinically evident lipodystrophy .
comparative data in the study groups with and without pll are also delineated in table 1 .
all patients were withdrawn from any medicines used to treat diabetes or dyslipidemia for 1 to 3 weeks so that they could be studied in the untreated state .
all patients denied positivity for hiv and explicitly denied that any other family members had the appearance or diagnosis of lipodystrophy to their knowledge .
none of the patients engaged in heavy alcohol use ( more than 2 drinks / day or 10 drinks / week ) , and orthostatic hypotension was excluded by sitting and standing blood pressure checks .
this study was approved by the institutional review boards of the institutions , and written informed consent was obtained in all patients .
patients were equilibrated on a metabolic ward on a diet consisting of 20% protein , 30% fat , and 50% carbohydrate for 3 days .
standard 75-g oral glucose tolerance tests were performed after an overnight fast . to assess glucose disposal rates ( gdrs ) ,
hyperinsulinemic - euglycemic clamps were performed at a maximally effective insulin concentration , as previously described ( 19 ) .
a catheter was inserted into the brachial vein , and a calibrated syringe pump was used to administer regular insulin in a square wave at a rate of 200 mu / m / min .
this infusion provided steady - state serum insulin levels that were maximally effective for promoting glucose uptake in skeletal muscle in patients with t2 dm and fully suppressing hepatic glucose production ( 19 ) . to prevent hypokalemia ,
a variable - rate infusion of a 20% dextrose solution was used to maintain the plasma glucose level at 90 mg / dl for at least 3 h , with plasma glucose levels assessed every 5 min throughout the clamp . during the final three 20-min intervals ,
the mean glucose infusion rate was used to calculate maximal glucose uptake for each individual .
whole - body glucose uptake was calculated based on the glucose infusion rate corrected for changes in the glucose pool size , assuming a distribution volume of 19% body weight and a pool fraction of 0.65 . under these conditions ,
the glucose infusion rate in milligrams per minute is equal to the gdr , and the data were normalized to total body weight ( kg ) or body surface area ( m ) .
if normally distributed , the data were expressed as mean  se , and the student t test was used to analyze whether differences between the patients with t2 dm with and without pll were statistically significant . if data were not normally distributed , values were presented as median ( first  third quartile ) , and statistical significance was determined using the nonparametric wilcoxon rank test .
statistical analysis was performed using sas 9.2 software ( sas institute , cary , nc ) and microsoft excel .
serum alanine aminotransaminase ( alt ) , aspartate aminotransaminase ( ast ) , and alkaline phosphatase ( alp ) values were expressed as a percentage of the clinical laboratory s established upper limit of the normal reference range .
all patients were females , and the race / ethnicity distribution was four european americans , four african americans , one asian american , and one hispanic american .
nine patients had t2 dm with variable severity of hyperglycemia , and one patient had prediabetes with impaired glucose tolerance ( igt ) .
as assessed by bmi ( kg / m ) , patients ranged from lean ( < 25 ) to overweight ( 2529.9 ) or obese ( > 30 ) .
loss of subcutaneous fat in the forearms only ( 4 patients ) and forearms and calves ( 3 patients ) were the most common presentations , with lipodystrophy involving forearms , calves , and thighs in one patient ( fig . 1 . ) and forearms , calves , thighs , and arms in two patients , with interscapular region involvement in one of these latter patients . with the loss of subcutaneous fat in the forearms and calves
, we can not rule out the possibility that there was a gain in fat above the level of lipoatrophy , for example , in the arms and thighs ( i.e. , when the arms and thighs were not affected by lipoatrophy ) .
patient 1 is shown with arrows indicating lipodystrophy of the forearms , thighs , and legs .
the patients with pll were matched with 10 patients without pll based on t2 dm status , race , age , and bmi .
accordingly , as reported in table 1 , subgroups with and without pll both consisted of nine t2 dm patients and one igt patient , and there were no statistically significant differences in mean bmi ( p = 0.94 ) , age ( p = 0.78 ) , and fasting glucose levels ( p = 0.19 ) .
in addition , the mean waist - to - hip ratio was equally elevated in both subgroups at 0.9 , and mean blood pressures were comparable ( data not shown ; p = ns ) .
however , the mean hba1c was somewhat higher in the pll patients ( 10.6  0.6% ) than in the control t2 dm subgroup ( 8.0  1.0% ; p < 0.05 ) .
importantly , the reported age of onset for t2 dm was earlier in the patients with pll than in the controls by more than a full decade ( 28.9  4.8 vs. 39.9  2.6 years , respectively ; p < 0.05 ) .
four patients were not cognizant of the lipodystrophy or thought it was a function of aging and did not have a clear notion regarding the onset of the pll .
six patients related that they believed they began to notice signs referable to the pll several years before the diagnosis of diabetes .
none of the patients without pll happened to have acanthosis nigricans , and the subgroups differed in other key clinical and metabolic parameters , as described below .
patients with t2 dm and pll were markedly more insulin - resistant than their diabetic counterparts without pll .
first , the mean fasting insulin level was increased by more than threefold in diabetic patients with ppl than in patients without pll ( 56  12 vs. 18  3 u / ml , p < 0.05 ; table 1 ) . more importantly , maximal gdrs during hyperinsulinemic clamps were significantly lower in the pll group ( 179.6  29.14 vs. 404.4  57.7 mg / min , p < 0.05 ) .
when normalized by body weight , gdr was reduced by 50% in t2 dm with pll compared with the control t2 dm patients ( 2.3  0.4 vs. 4.7  0.7 mg / kg / min , p < 0.05 ; fig .
2a ) and by 53% when normalized by body surface area ( 96.7  15.05 vs. 206.3 mg / m / min , p < 0.05 ; data not shown ) . these gdr values represent the combination of insulin - mediated and non - insulin  mediated glucose uptake rates . to derive values for insulin - mediated glucose uptake
, we subtracted 1.6 mg / kg / min , the previously determined rate of non - insulin  mediated glucose uptake at euglycemia in patients with diabetes and those without diabetes ( 20,21 ) , from the measured gdr values normalized by weight ( mg / kg / min ) in each subject .
patients with t2 dm and pll had little or no insulin - mediated glucose uptake during the clamps ( 0.6  0.4 mg / kg / min ) , and the mean value was reduced by 80% compared with the diabetes subgroup without pll ( 3.1  0.8 mg / kg / min , p < 0.05 ) . comparison of gdr and total triglycerides and cholesterol . a : gdrs were assessed using the hyperinsulinemic - euglycemic clamp technique and normalized per kilogram of body weight .
mean  se values were significantly lower in 10 patients with t2 dm and pll ( t2dm+pll ) compared with 10 patients with common t2 dm ( 2.26  0.42 vs. 4.74  0.77 mg / min / kg ; p < 0.05 ) .
b : in each subject , the value for non - insulin  mediated glucose disposal ( 1.6 mg / min / kg ; see insulin resistance : gdrs and fasting insulin levels ) was subtracted from the total gdr during the clamp to obtain the insulin - mediated gdr .
the mean  se value for insulin mediated glucose uptake in t2dm+pll was minimal and markedly reduced compared with common t2 dm ( 0.64  0.42 vs. 3.12  0.77 mg / min / kg ; p < 0.05 ) .
c : the mean  se value for triglycerides was increased in 10 patients with t2 dm and pll ( t2dm+pll ) compared with 10 patients with common t2 dm ( 543  175 vs. 134  28 mg / dl ; p < 0.05 ) .
d : mean  se levels of total cholesterol were statistically similar in comparing the t2 dm groups with and without pll ( 223  14 vs. 184  17 mg / dl ; p = 0.10 ) .
fasting triglyceride levels were elevated ( i.e. , > 150 mg / dl ) in 9 of the 10 patients with pll , with values ranging from 106 to 2,050 mg / dl . as shown in fig . 2c
, the median triglyceride level was markedly elevated by more than threefold in the pll patients compared with patients without pll , with values of 400 ( 232491 ) vs. 129 ( 95156 ) mg / dl , respectively ( p < 0.05 ) .
levels of total cholesterol were statistically similar ( p = 0.10 ) between the two subgroups ( fig .
values for alt , ast , and alp were expressed as a percentage of the laboratory s upper limit of the normal reference range .
although liver function tests were not available in all patients , alt and ast levels were elevated above the normal range in most of the patients with t2 dm and pll ( fig .
3 ) , and mean values were significantly increased by more than twofold when compared with the t2 dm patients without pll ( ast : 1.31  0.20- vs. 0.56  0.03-times the upper limit of normal , p < 0.05 ; and alt : 1.83  0.28- vs. 0.55  0.05-times the upper limit of normal , p < 0.05 ; respectfully ) . in contrast , mean values for alp were similar in the two subgroups ( 0.64  0.11- vs. 0.62  0.07-times the upper limit of normal , p = 0.87 ) . the mean total bilirubin value was increased in the pll group ( 0.98  0.10 vs. 0.57  0.05 iu / l , p < 0.05 ; fig .
3 ) ; however , the mean value in the pll subgroup remained within the normal range ( 0.11.1
values for ast ( a ) , alt ( b ) , and alp ( c ) were expressed as percentage of upper limit of the normal reference range and for total bilirubin ( d ) as iu / l .
all panels compare mean  se values in patients with t2 dm and pll ( t2dm+pll ) and in patients with common t2 dm .
the mean was statistically increased in t2dm+pll for ast , alt , and total bilirubin ( all p < 0.05 ) but not for alp ( p = ns ) .
all patients were females , and the race / ethnicity distribution was four european americans , four african americans , one asian american , and one hispanic american .
nine patients had t2 dm with variable severity of hyperglycemia , and one patient had prediabetes with impaired glucose tolerance ( igt ) .
as assessed by bmi ( kg / m ) , patients ranged from lean ( < 25 ) to overweight ( 2529.9 ) or obese ( > 30 ) .
loss of subcutaneous fat in the forearms only ( 4 patients ) and forearms and calves ( 3 patients ) were the most common presentations , with lipodystrophy involving forearms , calves , and thighs in one patient ( fig . 1 . ) and forearms , calves , thighs , and arms in two patients , with interscapular region involvement in one of these latter patients . with the loss of subcutaneous fat in the forearms and calves
, we can not rule out the possibility that there was a gain in fat above the level of lipoatrophy , for example , in the arms and thighs ( i.e. , when the arms and thighs were not affected by lipoatrophy ) .
patient 1 is shown with arrows indicating lipodystrophy of the forearms , thighs , and legs .
the patients with pll were matched with 10 patients without pll based on t2 dm status , race , age , and bmi .
accordingly , as reported in table 1 , subgroups with and without pll both consisted of nine t2 dm patients and one igt patient , and there were no statistically significant differences in mean bmi ( p = 0.94 ) , age ( p = 0.78 ) , and fasting glucose levels ( p = 0.19 ) .
in addition , the mean waist - to - hip ratio was equally elevated in both subgroups at 0.9 , and mean blood pressures were comparable ( data not shown ; p = ns ) .
however , the mean hba1c was somewhat higher in the pll patients ( 10.6  0.6% ) than in the control t2 dm subgroup ( 8.0  1.0% ; p < 0.05 ) .
importantly , the reported age of onset for t2 dm was earlier in the patients with pll than in the controls by more than a full decade ( 28.9  4.8 vs. 39.9  2.6 years , respectively ; p < 0.05 ) .
four patients were not cognizant of the lipodystrophy or thought it was a function of aging and did not have a clear notion regarding the onset of the pll .
six patients related that they believed they began to notice signs referable to the pll several years before the diagnosis of diabetes .
none of the patients without pll happened to have acanthosis nigricans , and the subgroups differed in other key clinical and metabolic parameters , as described below .
patients with t2 dm and pll were markedly more insulin - resistant than their diabetic counterparts without pll .
first , the mean fasting insulin level was increased by more than threefold in diabetic patients with ppl than in patients without pll ( 56  12 vs. 18  3 u / ml , p < 0.05 ; table 1 ) .
more importantly , maximal gdrs during hyperinsulinemic clamps were significantly lower in the pll group ( 179.6  29.14 vs. 404.4  57.7 mg / min , p < 0.05 ) .
when normalized by body weight , gdr was reduced by 50% in t2 dm with pll compared with the control t2 dm patients ( 2.3  0.4 vs. 4.7  0.7 mg / kg / min , p < 0.05 ; fig .
2a ) and by 53% when normalized by body surface area ( 96.7  15.05 vs. 206.3 mg / m / min , p < 0.05 ; data not shown ) .
these gdr values represent the combination of insulin - mediated and non - insulin  mediated glucose uptake rates . to derive values for insulin - mediated glucose uptake , we subtracted 1.6 mg / kg / min , the previously determined rate of non - insulin  mediated glucose uptake at euglycemia in patients with diabetes and those without diabetes ( 20,21 ) , from the measured gdr values normalized by weight ( mg / kg / min ) in each subject .
patients with t2 dm and pll had little or no insulin - mediated glucose uptake during the clamps ( 0.6  0.4 mg / kg / min ) , and the mean value was reduced by 80% compared with the diabetes subgroup without pll ( 3.1  0.8 mg / kg / min , p < 0.05 ) .
a : gdrs were assessed using the hyperinsulinemic - euglycemic clamp technique and normalized per kilogram of body weight .
mean  se values were significantly lower in 10 patients with t2 dm and pll ( t2dm+pll ) compared with 10 patients with common t2 dm ( 2.26  0.42 vs. 4.74  0.77 mg / min / kg ; p < 0.05 ) .
b : in each subject , the value for non - insulin  mediated glucose disposal ( 1.6 mg / min / kg ; see insulin resistance : gdrs and fasting insulin levels ) was subtracted from the total gdr during the clamp to obtain the insulin - mediated gdr . the mean  se value for insulin mediated glucose uptake in t2dm+pll was minimal and markedly reduced compared with common t2 dm ( 0.64  0.42 vs. 3.12  0.77 mg / min / kg ; p < 0.05 ) .
c : the mean  se value for triglycerides was increased in 10 patients with t2 dm and pll ( t2dm+pll ) compared with 10 patients with common t2 dm ( 543  175 vs. 134  28 mg / dl ; p < 0.05 ) .
d : mean  se levels of total cholesterol were statistically similar in comparing the t2 dm groups with and without pll ( 223  14 vs. 184  17 mg / dl ; p = 0.10 ) .
fasting triglyceride levels were elevated ( i.e. , > 150 mg / dl ) in 9 of the 10 patients with pll , with values ranging from 106 to 2,050 mg / dl .
2c , the median triglyceride level was markedly elevated by more than threefold in the pll patients compared with patients without pll , with values of 400 ( 232491 ) vs. 129 ( 95156 ) mg / dl , respectively ( p < 0.05 ) .
levels of total cholesterol were statistically similar ( p = 0.10 ) between the two subgroups ( fig .
values for alt , ast , and alp were expressed as a percentage of the laboratory s upper limit of the normal reference range .
although liver function tests were not available in all patients , alt and ast levels were elevated above the normal range in most of the patients with t2 dm and pll ( fig .
3 ) , and mean values were significantly increased by more than twofold when compared with the t2 dm patients without pll ( ast : 1.31  0.20- vs. 0.56  0.03-times the upper limit of normal , p < 0.05 ; and alt : 1.83  0.28- vs. 0.55  0.05-times the upper limit of normal , p < 0.05 ; respectfully ) . in contrast , mean values for alp were similar in the two subgroups ( 0.64  0.11- vs. 0.62  0.07-times the upper limit of normal , p = 0.87 ) .
the mean total bilirubin value was increased in the pll group ( 0.98  0.10 vs. 0.57  0.05 iu / l , p < 0.05 ; fig .
3 ) ; however , the mean value in the pll subgroup remained within the normal range ( 0.11.1
values for ast ( a ) , alt ( b ) , and alp ( c ) were expressed as percentage of upper limit of the normal reference range and for total bilirubin ( d ) as iu / l .
all panels compare mean  se values in patients with t2 dm and pll ( t2dm+pll ) and in patients with common t2 dm .
the mean was statistically increased in t2dm+pll for ast , alt , and total bilirubin ( all p < 0.05 ) but not for alp ( p = ns ) .
we have described both a new form of lipodystrophy and a new phenotype of t2 dm .
patients with t2 dm and pll are distinguished by 1 ) the presence of t2 dm or prediabetes , 2 ) symmetrical lipodystrophy of the forearms , or forearms plus calves , or less commonly , whole limbs , and 3 ) acanthosis nigricans .
metabolically , these patients have profound insulin resistance , with little or no measurable insulin - mediated glucose disposal during hyperinsulinemic clamps . when compared with the control t2 dm patients , the pll patients will often have greater elevations of hepatic transaminases , suggesting more pronounced hepatic steatosis and more marked hypertriglyceridemia , and report the onset of t2 dm a full decade earlier ( at 29 years ) .
t2 dm with pll can affect patients identifying with multiple ethnic and racial groups and appears to most commonly occur in women .
the pattern of fat loss is dissimilar from that reported for known forms of lipodystrophy with any consistency , and t2 dm with pll does not conform with entities that are conventionally categorized into the two - by - two , congenital versus acquired , generalized versus partial , diagnostic scheme .
the lipodystrophy is certainly partial and appears to be acquired , based on the lack of family history and its onset in adulthood . in the conventional scheme ,
the only form of apl is barraquer - simons syndrome , with patients who present with cephalocaudal loss of subcutaneous fat in the face , neck , arms , and thorax , accompanied by expansion , not loss , of adipose tissue in the lower extremities .
in addition , although these patients can develop a membranoproliferative glomerulonephritis , they seldom have t2 dm and the other metabolic abnormalities associated with severe insulin resistance ( 15 ) .
fpl represents a heterogeneous group of autosomal - dominant disorders with onset of lipodystrophy around puberty .
the pattern of lipodystrophy in the most common form , the dunnigan variety , involves the limbs and the trunk , often accompanied by increased adipose in the neck and face .
the kobberling variety of fpl involves women , often with t2 dm ; however , lipodystrophy consistently involves the limbs and gluteal region , and patients report onset in childhood ( 22 ) .
these features of apl and fpl stand in contrast to patients with t2 dm and pll in whom lipodystrophy primarily involves the distal extremities ( forearms or forearms plus calves ) , with no gluteal or anterior thorax involvement , in whom there is onset of lipodystrophy in adulthood without a family history , and in whom acanthosis nigricans and severe metabolic manifestations of insulin resistance are consistently observed .
although specific gene mutations have been reported in patients with fpl ( lmna , ppar , caveolin-1 ) ( 25 ) , the characteristics of t2 dm and pll do not conform to a monogenic or familial disease .
t2 dm and pll represent a distinct lipodystrophy phenotype based on current knowledge , but it is possible that with greater recognition of more subtle forms of apl and fpl and a more comprehensive understanding of the relationship between gene mutations and clinical manifestations , the conventional diagnostic scheme may no longer suffice . in this scenario , certain patients with apl , fpl , and t2 dm with pll may be found to share a common pathophysiology necessitating a reconstruction of the diagnostic framework . to illustrate this point ,
several studies have indicated that fpl may have a greater prevalence than previously thought due to lack of recognition of subtle forms .
patients in one study were screened for lipodystrophy and/or android body habitus , insulin resistance , or altered glucose tolerance .
the investigators then tested all patients with one or more of these characteristics for known gene mutations causing fpl ( 23 ) and demonstrated that several patients with mutations and associated metabolic features lacked lipodystrophy on physical examination ( 23 ) .
a more recent study showed that screening all nonobese patients with t2 dm for known fpl mutations increased its prevalence > 400-fold from their baseline assessment ( 24 ) .
both of these studies suggest strongly that there is an underestimation of prevalence and variability in clinical presentation for the partial lipodystrophies . from another perspective , t2 dm and pll represent a new phenotype that further exemplifies the heterogeneous nature of t2 dm . it is tempting to hypothesize that fat loss in t2 dm and pll is an extreme manifestation of adipose tissue dysfunction generally observed in patients with metabolic syndrome and t2 dm , which features macrophage infiltration , fibrosis , inflammation , and dysregulated secretion of adipocytokines ( eg , leptin , adiponectin , and resistin ) . in t2 dm with and without pll ,
adipose tissue defects lead to ectopic lipid accumulation in other tissues such as liver ( 25 ) .
these considerations suggest that patients with insulin resistance and t2 dm may exist along a continuum , with some patients having more subtle or subclinical diminution of subcutaneous fat in the distal extremities .
given the history in several patients that the lipodystrophy preceded the diagnosis of diabetes and that one patient had prediabetes , any normoglycemic patient presenting with pll should be monitored closely for the eventual development of diabetes . in any event , more detailed studies of patients with t2 dm and pll compared with patients without pll are needed to elucidate pathophysiology , and additional reports are needed to more precisely define t2 dm with pll as a clinical entity .
the profound degree of insulin resistance and lack of insulin - mediated glucose uptake should be considered in the choices and doses of antidiabetic medications , and careful evaluation and aggressive therapy for marked hypertriglyceridemia and steatohepatitis should be undertaken . along these same lines , promising results
have been observed with leptin replacement therapy in patients with several types of lipodystrophy ( 2628 ) .
for example , a reduction in serum triglycerides and intrahepatic lipid content was demonstrated in patients with fpl after 6 months of metreleptin treatment ( 28 ) .
it remains to be seen whether pharmacological administration of leptin can ameliorate glycemic control , insulin resistance , hypertriglyceridemia , and hepatic steatosis in t2 dm with pll .
even so , partial pll and the accompanying severity of metabolic abnormalities may not be rare .
for the most part , patients in this study presented with t2 dm and were initially suspected to have pll by instinctively inspecting the forearms of each new patient during the introductory shaking of hands .
certainly , all t2 dm patients with overt hypertriglyceridemia and hepatic transaminase elevations or with high insulin requirements should be examined closely for pll .
thus , t2 dm with pll represents a previously unrecognized phenotype of lipodystrophy and of diabetes .
these patients exhibit symmetrical lipodystrophy of the distal limbs , acanthosis nigricans , earlier onset t2 dm , and marked insulin resistance with little insulin - mediated glucose uptake , as well as hypertriglyceridemia and hepatic transaminase elevations that are greater in severity than observed in patients with commonly occurring t2 dm .
 objectivelipodystrophies are categorized by the extent of fat loss ( generalized vs. partial ) and by inheritance ( congenital vs. acquired ) . 
 we examined whether a group of patients with partial lipodystrophy of the limbs ( pll ) , type 2 diabetes mellitus ( t2 dm ) , and an absence of a family history of lipodystrophy constitute a new clinical subtype.research design and methodsten women with t2 dm and pll were identified in academic diabetes clinics and were matched by age , sex , bmi , ethnicity , and diabetes status with 10 women with control t2 dm without lipodystrophy . 
 all patients were characterized by clinical evaluation and hyperinsulinemic clamp.resultspatients with t2 dm and pll exhibited symmetrical loss of subcutaneous fat in forearms , or forearms plus calves , and acanthosis nigricans . 
 maximally stimulated glucose disposal rates were markedly reduced by 56% in the t2 dm with pll group compared with the control t2 dm patients , whether normalized by body weight or surface area . 
 most pll patients exhibited little or no insulin - mediated glucose uptake after subtraction of non - insulin  mediated glucose uptake . 
 the t2 dm with pll group also had greater elevations in hepatic transaminases and triglycerides and earlier onset of diabetes compared with control t2dm.conclusionst2dm with pll represents a previously unrecognized phenotype of lipodystrophy and of t2 dm . these t2 dm patients exhibit symmetrical lipodystrophy of the distal limbs , acanthosis nigricans , marked insulin resistance with little insulin - mediated glucose uptake , hypertriglyceridemia , and hepatic transaminase elevations , which are greater in severity than observed in patients with common t2 dm . 
RESEARCH DESIGN AND METHODS
Subject selection
Protocol and glucose clamp studies
Statistical analysis
RESULTS
Characteristics of patients
Insulin resistance: GDRs and fasting insulin levels
Serum triglycerides and cholesterol
Liver function tests
CONCLUSIONS