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Kenneth Cusi, Assistant
Professor; M.D.,
Telephone: (210) 567-6708 E-mail:
cusi@uthscsa.edu
Insulin resistance, type 2
diabetes and fatty liver disease
T2DM is a major public health
problem, but less well recognized is that obesity and T2DM are fueling
another “silent epidemic”: non-alcoholic fatty liver disease (NAFLD). NAFLD
is a chronic liver condition associated with insulin resistance, impaired
glucose tolerance or type 2 diabetes (T2DM) and hepatic fat accumulation,
ranging from simple steatosis to severe steatohepatitis with necrosis and
inflammation (NASH) and eventually fibrosis. We are currently working
at understanding the molecular mechanisms that lead to non-alcoholic fatty
liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in humans.
Our recent success (Belfort et al, New England J Medicine, November 2006)
at finding the first effective treatment for NASH in patients with type
2 diabetes (T2DM) has radically changed the approach to the diagnosis and
management of this common condition. However, the molecular abnormalities
that lead to NASH, and how pioglitazone works in patients with NASH, remain
poorly understood. Understanding this will be essential to prevent
liver damage and tackle a growing public health problem as NAFLD appears
to affect 1 out of 3 adults in the United States.
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Fernandez
M, Triplitt C, Wajcberg E, Sriwijilkamol AA, Musi N, Cusi K, Defronzo R,
Cersosimo E.
Addition of Pioglitazone and Ramipril to Intensive Insulin Therapy
in Type 2 Diabetic Patients Improves Vascular Dysfunction by Different
Mechanisms.
Diabetes Care. 2007 Oct 1; [Epub ahead of print]
PMID: 17909084
Balas
B, Belfort R, Harrison SA, Darland C, Finch J, Schenker S, Gastaldelli
A, Cusi K.
Pioglitazone treatment increases whole body fat but not total body
water in patients with non-alcoholic steatohepatitis.
J Hepatol. 2007 Oct;47(4):565-70. Epub 2007 May 24.
PMID: 17560678
Berria
R, Glass L, Mahankali A, Miyazaki Y, Monroy A, De Filippis E, Cusi K, Cersosimo
E, Defronzo RA, Gastaldelli A.
Reduction in hematocrit and hemoglobin following pioglitazone treatment
is not hemodilutional in Type II diabetes mellitus.
Clin Pharmacol Ther. 2007 Sep;82(3):275-81. Epub 2007 Mar 14.
PMID: 17361126
Gastaldelli
A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, Buzzigoli E, Sironi
AM, Cersosimo E, Ferrannini E, Defronzo RA.
Relationship between hepatic/visceral fat and hepatic insulin resistance
in nondiabetic and type 2 diabetic subjects.
Gastroenterology. 2007 Aug;133(2):496-506. Epub 2007 May 1.
PMID: 17681171
Cusi
K, Kashyap S, Gastaldelli A, Bajaj M, Cersosimo E.
Effects on insulin secretion and insulin action of a 48-h reduction
of plasma free fatty acids with acipimox in nondiabetic subjects genetically
predisposed to type 2 diabetes.
Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1775-81. Epub
2007 Feb 13.
PMID: 17299078
Ruan
C, Yang SH, Cusi K, Gao F, Clarke GD.
Contrast-enhanced first-pass myocardial perfusion magnetic resonance
imaging with parallel acquisition at 3.0 Tesla.
Invest Radiol. 2007 Jun;42(6):352-60.
PMID: 17507805
Balas
B, Baig MR, Watson C, Dunning BE, Ligueros-Saylan M, Wang Y, He YL, Darland
C, Holst JJ, Deacon CF, Cusi K, Mari A, Foley JE, DeFronzo RA.
The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous
glucose production and enhances islet function after single-dose administration
in type 2 diabetic patients.
J Clin Endocrinol Metab. 2007 Apr;92(4):1249-55. Epub 2007 Jan
23.
PMID: 17244786
De
Filippis E, Cusi K, Ocampo G, Berria R, Buck S, Consoli A, Mandarino LJ.
Exercise-induced improvement in vasodilatory function accompanies increased
insulin sensitivity in obesity and type 2 diabetes mellitus.
J Clin Endocrinol Metab. 2006 Dec;91(12):4903-10. Epub 2006
Oct 3.
PMID: 17018657
Belfort
R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli
A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C,
DeFronzo R, Bannayan GA, Schenker S, Cusi K.
A placebo-controlled trial of pioglitazone in subjects with nonalcoholic
steatohepatitis.
N Engl J Med. 2006 Nov 30;355(22):2297-307.
PMID: 17135584
Berria
R, Gastaldelli A, Lucidi S, Belfort R, De Filippis E, Easton C, Brytzki
R, Cusi K, Jovanovic L, DeFronzo R.
Reduction in hematocrit level after pioglitazone treatment is correlated
with decreased plasma free testosterone level, not hemodilution, in women
with polycystic ovary syndrome.
Clin Pharmacol Ther. 2006 Aug;80(2):105-14. Epub 2006 Jun 30.
PMID: 16890572
Ruan
C, Yang S, Clarke GD, Amurao MR, Partyka SR, Bradley YC, Cusi K.
First-pass contrast-enhanced myocardial perfusion MRI using a maximum
up-slope parametric map.
IEEE Trans Inf Technol Biomed. 2006 Jul;10(3):574-80.
PMID: 16871727
Belfort
R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, Defronzo
RA, Cusi K.
Dose-response effect of elevated plasma free fatty acid on insulin
signaling.
Diabetes. 2005 Jun;54(6):1640-8.
PMID: 15919784
Richardson
DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA,
Jenkinson CP, Mandarino LJ.
Lipid infusion decreases the expression of nuclear encoded mitochondrial
genes and increases the expression of extracellular matrix genes in human
skeletal muscle.
J Biol Chem. 2005 Mar 18;280(11):10290-7. Epub 2004 Dec 14.
PMID: 15598661
Kashyap
SR, Belfort R, Berria R, Suraamornkul S, Pratipranawatr T, Finlayson J,
Barrentine A, Bajaj M, Mandarino L, DeFronzo R, Cusi K.
Discordant effects of a chronic physiological increase in plasma FFA
on insulin signaling in healthy subjects with or without a family history
of type 2 diabetes.
Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E537-46. Epub
2004 May 4.
PMID: 15126243
Bajaj
M, Suraamornkul S, Kashyap S, Cusi K, Mandarino L, DeFronzo RA.
Sustained reduction in plasma free fatty acid concentration improves
insulin action without altering plasma adipocytokine levels in subjects
with strong family history of type 2 diabetes.
J Clin Endocrinol Metab. 2004 Sep;89(9):4649-55.
PMID: 15356076
Civitarese
AE, Jenkinson CP, Richardson D, Bajaj M, Cusi K, Kashyap S, Berria R, Belfort
R, DeFronzo RA, Mandarino LJ, Ravussin E.
Adiponectin receptors gene expression and insulin sensitivity in non-diabetic
Mexican Americans with or without a family history of Type 2 diabetes.
Diabetologia. 2004 May;47(5):816-20. Epub 2004 Apr 23.
PMID: 15105989
Kashyap
S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W,
Bajaj M, Mandarino L, DeFronzo R, Cusi K.
A sustained increase in plasma free fatty acids impairs insulin secretion
in nondiabetic subjects genetically predisposed to develop type 2 diabetes.
Diabetes. 2003 Oct;52(10):2461-74.
PMID: 14514628
Patti
ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane
I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R,
Finlayson J, Kahn CR, Mandarino LJ.
Coordinated reduction of genes of oxidative metabolism in humans with
insulin resistance and diabetes: Potential role of PGC1 and NRF1.
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8466-71. Epub 2003
Jun 27.
PMID: 12832613
Bajaj
M, Pratipanawatr T, Berria R, Pratipanawatr W, Kashyap S, Cusi K, Mandarino
L, DeFronzo RA.
Free fatty acids reduce splanchnic and peripheral glucose uptake in
patients with type 2 diabetes.
Diabetes. 2002 Oct;51(10):3043-8.
PMID: 12351445
Bajaj
M, Berria R, Pratipanawatr T, Kashyap S, Pratipanawatr W, Belfort R, Cusi
K, Mandarino L, DeFronzo RA.
Free fatty acid-induced peripheral insulin resistance augments splanchnic
glucose uptake in healthy humans.
Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E346-52.
PMID: 12110541
Pratipanawatr
T, Pratipanawatr W, Rosen C, Berria R, Bajaj M, Cusi K, Mandarino L, Kashyap
S, Belfort R, DeFronzo RA.
Effect of IGF-I on FFA and glucose metabolism in control and type 2
diabetic subjects.
Am J Physiol Endocrinol Metab. 2002 Jun;282(6):E1360-8.
PMID: 12006367
Miyazaki
Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ,
DeFronzo RA.
Effect of pioglitazone on abdominal fat distribution and insulin sensitivity
in type 2 diabetic patients.
J Clin Endocrinol Metab. 2002 Jun;87(6):2784-91.
PMID: 12050251
Pratipanawatr
T, Cusi K, Ngo P, Pratipanawatr W, Mandarino LJ, DeFronzo RA.
Normalization of plasma glucose concentration by insulin therapy improves
insulin-stimulated glycogen synthesis in type 2 diabetes.
Diabetes. 2002 Feb;51(2):462-8.
PMID: 11812756
Miyazaki
Y, Glass L, Triplitt C, Matsuda M, Cusi K, Mahankali A, Mahankali S, Mandarino
LJ, DeFronzo RA.
Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism
in Type II diabetic patients.
Diabetologia. 2001 Dec;44(12):2210-9.
PMID: 11793023
Pratipanawatr
W, Pratipanawatr T, Cusi K, Berria R, Adams JM, Jenkinson CP, Maezono K,
DeFronzo RA, Mandarino LJ.
Skeletal muscle insulin resistance in normoglycemic subjects with a
strong family history of type 2 diabetes is associated with decreased insulin-stimulated
insulin receptor substrate-1 tyrosine phosphorylation.
Diabetes. 2001 Nov;50(11):2572-8.
PMID: 11679436
Iozzo
P, Pratipanawatr T, Pijl H, Vogt C, Kumar V, Pipek R, Matsuda M, Mandarino
LJ, Cusi KJ, DeFronzo RA.
Physiological hyperinsulinemia impairs insulin-stimulated glycogen
synthase activity and glycogen synthesis.
Am J Physiol Endocrinol Metab. 2001 May;280(5):E712-9.
PMID: 11287353
Cusi
KJ, Pratipanawatr T, Koval J, Printz R, Ardehali H, Granner DK, Defronzo
RA, Mandarino LJ.
Exercise increases hexokinase II mRNA, but not activity in obesity
and type 2 diabetes.
Metabolism. 2001 May;50(5):602-6.
PMID: 11319725
Miyazaki
Y, Mahankali A, Matsuda M, Glass L, Mahankali S, Ferrannini E, Cusi K,
Mandarino LJ, DeFronzo RA.
Improved glycemic control and enhanced insulin sensitivity in type
2 diabetic subjects treated with pioglitazone.
Diabetes Care. 2001 Apr;24(4):710-9.
PMID: 11315836
Cusi
K, Cukier S, DeFronzo RA, Torres M, Puchulu FM, Redondo JC.
Vanadyl sulfate improves hepatic and muscle insulin sensitivity in
type 2 diabetes.
J Clin Endocrinol Metab. 2001 Mar;86(3):1410-7.
PMID: 11238540
Cusi
K, DeFronzo R.
Recombinant human insulin-like growth factor I treatment for 1 week
improves metabolic control in type 2 diabetes by ameliorating hepatic and
muscle insulin resistance.
J Clin Endocrinol Metab. 2000 Sep;85(9):3077-84.
PMID: 10999789
Osman
AA, Pendergrass M, Koval J, Maezono K, Cusi K, Pratipanawatr T, Mandarino
LJ.
Regulation of MAP kinase pathway activity in vivo in human skeletal
muscle.
Am J Physiol Endocrinol Metab. 2000 Jun;278(6):E992-9.
PMID: 10827000
Cusi
K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo
RA, Kahn CR, Mandarino LJ.
Insulin resistance differentially affects the PI 3-kinase- and MAP
kinase-mediated signaling in human muscle.
J Clin Invest. 2000 Feb;105(3):311-20.
PMID: 10675357
Cusi
K, Consoli A, DeFronzo RA.
Metabolic effects of metformin on glucose and lactate metabolism in
noninsulin-dependent diabetes mellitus.
J Clin Endocrinol Metab. 1996 Nov;81(11):4059-67.
PMID: 8923861
Mandarino
LJ, Printz RL, Cusi KA, Kinchington P, O'Doherty RM, Osawa H, Sewell C,
Consoli A, Granner DK, DeFronzo RA.
Regulation of hexokinase II and glycogen synthase mRNA, protein, and
activity in human muscle.
Am J Physiol. 1995 Oct;269(4 Pt 1):E701-8. Erratum in: Am J
Physiol 1996 Jan;270(1 Pt 1):section E followi.
PMID: 7485484
