Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/ MetS/T2DM), and their adverse... more Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/ MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet-dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver-to-muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle. The ensuing hyperinsulinemia further activates hepatic aPKC, which first blocks the ability of Akt to suppress gluconeogenic enzyme expression, and later impairs Akt activation, further increasing hepatic glucose production. Recent findings suggest that hepatic aPKC also increases a proteolytic enzyme that degrades insulin receptors. Fortunately, all hepatic aberrations and muscle impairments are prevented/reversed by inhibition or deficiency of hepatic aPKC. But, in the absence of treatment, hyperinsulinemia induces adverse events, some by using "spare receptors" to bypass receptor defects. Thus, in brain, hyperinsulinemia increases Aβ-plaque
American Journal of Physiology-Endocrinology and Metabolism, 2009
Assessing insulin resistance in rodent models gives insight into mechanisms that cause type 2 dia... more Assessing insulin resistance in rodent models gives insight into mechanisms that cause type 2 diabetes and the metabolic syndrome. The hyperinsulinemic euglycemic glucose clamp, the reference standard for measuring insulin sensitivity in humans and animals, is labor intensive and technically demanding. A number of simple surrogate indexes of insulin sensitivity/resistance have been developed and validated primarily for use in large human studies. These same surrogates are also frequently used in rodent studies. However, in general, these indexes have not been rigorously evaluated in animals. In a recent validation study in mice, we demonstrated that surrogates have a weaker correlation with glucose clamp estimates of insulin sensitivity/resistance than in humans. This may be due to increased technical difficulties in mice and/or intrinsic differences between human and rodent physiology. To help distinguish among these possibilities, in the present study, using data from rats substan...
HANSEN, BARBARA C,HEIDIKORTMEYERAND NONILBODKIN. Preventionofobesity inmiddle-aged monkey: foodin... more HANSEN, BARBARA C,HEIDIKORTMEYERAND NONILBODKIN. Preventionofobesity inmiddle-aged monkey: foodintake duringbodyweight clamp. ObesRes. Preventionof obesity andincreaseinlongevity inobesityprone rodents can be achieved by long-term moderate dietary restriction. In orderto examine thelikelihoodthat caloric restriction could have similar salutary effects in humans, rhesus monkeys, after reaching mature adult stature,were placedon aprotocolto clamp or stabilize body weight byweekly caloric adjustment. Furtherweight gain waspreventedby this caloric titrationprocedure, and thus middle-age onset obesity, which is very common in this species,was prevented. The present study analyzed daily food intake for six weight-clamped monkeys and six ad libitumfed age-matched animals over a 3-yearpeiiod,ages 18.5 to21.5 years. After approximately9 years ofcaloric restriction the daily calorie load to maintain stable adult body weight proved to be 40% less than the amount ingested by ad libitum fed animals. Calories per kg body weight did not differ significantly between the groups although the ad libitum fed animals were significantly fatter than theweight-clamped group. Preventionofobesity usingthis weight clamp protocolhas also maintained lower insulin levels and higher glucose tolerance in the restricted animals. 19953 (sUppl2):199~-204~.
Mortality and morbidity were examined in 117 laboratory-maintained rhesus monkeys studied over ap... more Mortality and morbidity were examined in 117 laboratory-maintained rhesus monkeys studied over approximately 25 years (8 dietary-restricted [DR] and 109 ad libitum-fed [AL] monkeys). During the study, 49 AL monkeys and 3 DR monkeys died. Compared with the DR monkeys, the AL monkeys had a 2.6-fold increased risk of death. Hyperinsulinemia led to a 3.7-fold increased risk of death (p , .05); concordantly, the risk of death decreased by 7%, per unit increase in insulin sensitivity (M). There was significant organ pathology in the AL at death. The age at median survival in the AL was approximately 25 years compared with 32 years in the DR. The oldest monkey was a diabetic female (AL) that lived to be 40 years of age. These results suggest that dietary restriction leads to an increased average age of death in primates, associated with the prevention of hyperinsulinemia and the mitigation of age-related disease.
Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbi... more Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbidity and increases median age of death. The present review is focused upon an ongoing study of sustained adult-onset calorie restriction, which has been underway for 15 years. Monkeys, initially calorie restricted at about 10 years of age, are now approximately 25 years old. The median life span of these restricted monkeys is increasing, now exceeding that of ad libitum (AL)-fed monkeys. In our laboratory, maximum life span for AL-fed monkeys appears to be about 40 years. Thus, whether CR can also increase maximal life span, as it does in rodents, cannot be determined for at least another 15 years. The earliest detectable positive benefit on morbidity in these monkeys was previously reported as the prevention of obesity. Current evidence, as reviewed here, suggests that much obesity-associated morbidity is also mitigated by sustained calorie restraint in nonhuman primates. Furthermore, probably because of the prevention of obesity, diabetes has also been prevented. Recent findings include the identification of extraordinary changes in the glycogen synthesis pathway, and on the phosphorylation of glycogen synthase in response to insulin. This calorie restriction-induced prevention of morbidity does not require excessive leanness, but is clearly present when body fat is within the normal range of 10 to 22%, and this is likely to be true in humans as well.
Inositols—Potential roles in insulin action and in diabetes: Evidence from insulin-resistant nonhuman primates
Birkhäuser Boston eBooks, 1996
... Labeled inosi-tol has been shown to be taken up by an active transport or carrier-mediated pr... more ... Labeled inosi-tol has been shown to be taken up by an active transport or carrier-mediated process and incorporated into phosphoinositides, and within several hours it was Correspondence: Dr. Heidi K. Ortmeyer, Obesity and Diabetes Research Center ... 70 Mato et al. ...
Aging has been shown to have an effect on the capacity to differentiate preadipocytes and on the ... more Aging has been shown to have an effect on the capacity to differentiate preadipocytes and on the expression ofsome genes expressed in adipose tissue. The mRNA levels ofadipocyte differentiation-related genes were examined in rhesus monkeys (Macaca Mulatta) ranging in age from 7 to 30 years. The effect ofaging on the expression ofperoxisome proliferator activated receptor 'Y(PPAR'Y),adipocyte determination-and differentiation-dependentfactor lIsterol regulatory element binding protein 1 (ADDIISREBPl), CCAATlenhancer binding protein a (CIEBPa), lipoprotein lipase (LPL), GLUT4 glucose transporter, and adipsin were examined by slot blot analysis. Significant inverse correlations were observed between age and the mRNA levels ofPPAR'Y, ADDlISREBPl, LPL, and GLUT4. The coordinate downregulation ofthese genes may be linked to the declining fat mass ofsenescent animals. There was no correlation between age and the mRNA levels of adipsin. The mRNA levels ofthese genes were not correlated to body weight or fasting plasma insulin. These findings indicate that aging may have an effect on the adipocyte differentiation program and this effect appears to be gene specific.
The human insulin receptor has two isoforms derived from alternative splicing of exon 11 of the i... more The human insulin receptor has two isoforms derived from alternative splicing of exon 11 of the insulin receptor gene. The type B (containing exon 11, or exon 11 +) isoform binds insulin with twofold lower affinity than the type A (lacking exon 11, or exon 11-) isoform. In efforts to resolve the controversy over whether altered splicing is involved in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM), the spontaneously obese diabetic rhesus monkey, a unique model that is extraordinarily similar to human NIDDM, was used. Cross-sectional studies of insulin receptor mRNA splicing variants in vastus lateralis muscle were performed on 19 rhesus monkeys. When monkeys were divided into four groups based upon the known stages of progression to NIDDM: normal (normoglycemic/normoinsulinemic), prediabetic (normoglycemic/hyperinsulinemic), early NIDDM (hyperglycemic/hyperinsulinemic), and late NIDDM (hyperglycemic/ hypoinsulinemic), both hyperinsulinemic groups had significantly higher percentages of the exon 11-mRNA splicing variant compared to the normal (74.8±1.7 vs 59.0 ±2.3%; P < 0.005) and late NIDDM groups (74.8±1.7 vs 64.2±3.9%; P < 0.05). Our findings provide the first direct evidence linking hyperinsulinemia to alterations in insulin receptor mRNA splicing, and suggest that alterations of insulin receptor mRNA splicing in muscle is an early molecular marker that may play an important role in NIDDM.
Annals of the New York Academy of Sciences, Nov 1, 1999
Calorie restriction (CR) has previously been shown to unexpectedly induce a reversal of in vivo i... more Calorie restriction (CR) has previously been shown to unexpectedly induce a reversal of in vivo insulin action (phosphorylation instead of dephosphorylation) on skeletal muscle glycogen synthase (GS) in four out of six long-term calorie-restricted (CR) monkeys. The purpose of the present study was to determine whether this increase in Ka (concentration of glucose 6-phosphate [G6P] at which GS activity is half-maximal) during insulin is also present in very lean (VL) young adult monkeys maintained on a controlled feeding regimen. Muscle samples from 10 VL monkeys (10 ± 2% body fat; 7 years old) were obtained before and during a euglycemic hyperinsulinemic clamp and the Ka was determined and compared to the Ka of two other groups of monkeys, one matched in age but fully ad libitum (AL)-fed (n = 9, 8 ± 1 years old, 20 ± 3% body fat, p = 0.01 vs. VL monkeys), and the other our previously described weight-clamped long-term CR monkeys (n = 6, 20 ± 1 years old, 21 ± 2% body fat, p = 0.01 vs. VL monkeys). All of the AL monkeys had the expected decrease in Ka with insulin; however, similar to the 4 out of 6 CR monkeys, 7 out of 10 VL monkeys had an increase in Ka with insulin. The 11 monkeys with an increase in Ka (+Ka) (7 VL + 4 CR) were compared to the 14 monkeys with a decrease in Ka with insulin (-Ka) (3 VL + 2 CR + 9 AL). The +Ka monkeys had lower basal Ka (p = 0.0001), higher basal GS fractional activity (p = 0.0003), lower basal G6P content (p = 0.002), lower glycogen phosphorylase fractional activity (p = 0.01), and lower whole-body insulin-mediated glucose disposal rate (p < 0.05) than the-Ka monkeys. We conclude that the condition of steady-state restrained calorie intake (as in the CR monkeys and in the controlled feeding VL monkeys) produces the paradoxical action of in vivo insulin to phosphorylate muscle GS, and raises the possibility that the presence of the unusual response to insulin may serve as a marker in calorie-restrained individuals for the genotype of obesity, insulin resistance and/or Type 2 diabetes.
chiroand myo-Inositols are major components of the two inositol phosphoglycan mediators of insuli... more chiroand myo-Inositols are major components of the two inositol phosphoglycan mediators of insulin action. Previous work in this laboratory has shown hypo-chiroinositoluria in type H diabetic subjects and decreased chiroinositol in mediator prepared from skeletal-muscle biopsies of Pima Indian diabetic subjects together with increased myoinositol concentrations. Because mediator bioactivity was not previously examined, we decided to isolate the two types of insulin mediator from hemodialysate, urine, and autopsy muscle to investigate their bioactivity in control and type H diabetic subjects. Human mediator fractions were isolated at pH 2.0 and pH 1.3 from hemodialysate, urine, and autopsy muscle of type II diabetic subjects and nondiabetic control subjects. Mediators were assayed for bioactivity, and the relative chiroinositol/myo-inositol concentration ratio was determined for the mediator pH 2.0 samples by using HPLC or GC/MS. Regardless of source, the chiro-inositol-containing mediator pH 2.0 fractions from type H diabetic subjects were markedly less active than those from controls (50% or less) (P < 0.05). In addition, the chiro-inositol/myo-inositol ratio in samples from type H subjects was signficantly reduced (1/3-1/9) compared with controls (P < 0.05 for hemodialysate and P < 0.01 for muscle samples). In contrast, no difference in bioac
Glycogen phosphorylase activity and glycogen concentration in muscle of normal to overtly diabetic rhesus monkeys
PubMed, Feb 1, 1996
The effect of insulin to increase the activity of glycogen synthase (GS) in muscle has been well ... more The effect of insulin to increase the activity of glycogen synthase (GS) in muscle has been well documented, however, the effect of in vivo insulin to inactivate glycogen phosphorylase (GP) has not been previously shown. To determine the effects of insulin on glycogenolysis in rhesus monkeys, GP and glycogen were determined in muscle samples obtained under basal fasting and insulin-stimulated conditions during a euglycemic hyperinsulinemic clamp in a group of 27 monkeys ranging from normal to overtly diabetic (NIDDM) and compared to GS activity previously examined. The diabetic monkeys had lower basal and insulin-stimulated glycogen concentrations compared to the normal and hyperinsulinemic monkeys (p < 0.05). The response of GP activity ratio (AR) to insulin (delta) was inversely correlated to delta GS fractional velocity (fv) (r = -0.57, p < 0.002) in all of the monkeys. The AR of GP was inversely correlated to the fv of GS measured under insulin-stimulated conditions (r = -0.60, p < 0.05) in the 11 normal monkeys. In the normal group, the range in response of GS to insulin (delta GSfv) was previously shown to be 3-22%, with n = 6 < 11% ('low normals') and n = 5 > 11% ('high normals'). In the present study, the low normals were shown to have (1) higher delta GP independent activity and delta GP total activity compared to the high normals and hyperinsulinemic monkeys (p less than or equal to 0.05), (2) higher insulin-stimulated GP independent activity and GP total activity compared to the other three groups (p < 0.05), (3) higher insulin-stimulated GP activity ratio compared to the high normals and hyperinsulinemic monkeys (p < 0.05), (4) and lower whole-body insulin-mediated glucose disposal rates compared to the high normals (p < 0.05). We conclude that NIDDM is accompanied by low glycogen content in the muscle, and that some clinically normal monkeys have an alteration in insulin action on muscle GS, GP, and whole-body glucose disposal rates that may precede the development of hyperinsulinemia.
Obesity, the metabolic syndrome, and aging share several pathogenic features in both humans and n... more Obesity, the metabolic syndrome, and aging share several pathogenic features in both humans and non-human primates, including insulin resistance and inflammation. Since muscle and liver are considered key integrators of metabolism, we sought to determine in biopsies from lean and obese aging rhesus monkeys the nature of defects in insulin activation and, further, the potential for mitigation of such defects by an in vivo insulin sensitizer, rosiglitazone, and a thiazolidinedione activator of the peroxisome proliferator-activated receptor gamma. The peroxisome proliferator-activated receptor gamma agonist reduced hyperinsulinemia, improved insulin sensitivity, lowered plasma triglycerides and free fatty acids, and increased plasma adiponectin. In muscle of obese monkeys, previously shown to exhibit defective insulin signaling, the insulin sensitizer improved insulin activation of atypical protein kinase C (aPKC), the defective direct activation of aPKC by phosphatidylinositol (PI)-3,4,5-(PO 4) 3 , and 5 0-AMPactivated protein kinase and increased carnitine palmitoyltransferase-1 mRNA expression, but it did not improve insulin activation of insulin receptor substrate (IRS)-1-dependent PI 3-kinase (IRS-1=PI3K), protein kinase B, or glycogen synthase. We found that, although insulin signaling was impaired in muscle, insulin activation of IRS-1=PI3K, IRS-2=PI3K, protein kinase B, and aPKC was largely intact in liver and that rosiglitazone improved insulin signaling to aPKC in muscle by improving responsiveness to PI-3,4,5-(PO 4) 3. Antioxid. Redox Signal. 14, 207-219.
Long-Term Dietary Restriction in Older-Aged Rhesus Monkeys: Effects on Insulin Resistance
The Journals of Gerontology, May 1, 1995
Long-term dietary restriction to maintain constant body weight in adult rhesus monkeys prevents t... more Long-term dietary restriction to maintain constant body weight in adult rhesus monkeys prevents the development of impaired glucose tolerance, hyperglycemia, and noninsulin-dependent diabetes mellitus. We sought to determine whether these positive antidiabetogenic effects of reduced calorie intake with maintenance of normal lean body weight might be mediated through prevention of the development of insulin resistance. Insulin-stimulated glucose uptake was assessed by the euglycemic hyperinsulinemic clamp technique in seven older-aged rhesus monkeys (20.7 +/- 0.6 years) who had been dietary restricted for 9 +/- 2 years. Results were compared to seven ad libitum-fed nondiabetic monkeys of similar age (21.0 +/- 1.3 years). Results showed that the dietary restricted monkeys had significantly higher in vivo insulin action compared to the ad libitum-fed group (14.06 +/- 2.4 vs 7.75 +/- 0.9 mg/kg FFM/min, respectively; p &lt; .03). We conclude that long-term dietary restriction is an effective means of mitigating the development of significant insulin resistance in older-aged rhesus monkeys, and may be the mechanism underlying the prevention of Type II diabetes in this model.
Journal of basic and clinical physiology and pharmacology, 1998
In skeletal muscle of normal subjects, the concentration of glucose 6-phosphate (G6P) at which th... more In skeletal muscle of normal subjects, the concentration of glucose 6-phosphate (G6P) at which the activity of glycogen synthase (GS) is half maximal (Ka) is decreased by in vivo insulin, and the fractional activity is increased without a change in GS maximal activity (V max). We have shown that moderate chronic calorie restriction, previously shown in rodents to be effective in slowing aging, resulted in the prevention of obesity and type 2 diabetes in primates (rhesus monkeys, Macaca mulatto). However, unexpectedly, in a subgroup of calorierestricted monkeys, insulin during a euglycemic hyperinsulinemic clamp caused an unanticipated decrease in skeletal muscle GS fractional activity. These same monkeys had the lowest whole-body glucose disposal rate (M), the greatest increase in skeletal muscle G6P content and the greatest increase in skeletal muscle glycogen phosphorylase activity during the euglycemic hyperinsulinemic clamp compared to the remaining calorie-restricted monkeys with normal insulin action. To determine whether this highly unusual insulin-mediated decrease in GS fractional activity was due to increased phosphorylation (increased K a), we measured the activity of skeletal muscle GS at 9 different G6P concentrations before and during the euglycemic hyperinsulinemic clamp in 6 calorie-restricted monkeys. G6P K a increased (n=4) and V max decreased (n=5) during the clamp. Basal G6P K a was inversely
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