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  1. Article: A case for new therapy for diabetes, is it leptin?

    Kalra, Satya P

    Indian journal of endocrinology and metabolism

    2013  Volume 16, Issue Suppl 3, Page(s) S525–8

    Language English
    Publishing date 2013-03-26
    Publishing country India
    Document type Journal Article
    ZDB-ID 2600211-5
    ISSN 2230-9500 ; 2230-8210
    ISSN (online) 2230-9500
    ISSN 2230-8210
    DOI 10.4103/2230-8210.105566
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Should leptin replace insulin as a lifetime monotherapy for diabetes type 1 and 2?

    Kalra, Satya P

    Indian journal of endocrinology and metabolism

    2013  Volume 17, Issue Suppl 1, Page(s) S23–4

    Abstract: Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency ... ...

    Abstract Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency disrupts the relay of hypothalamic regulatory information along three descending pathways to the organs in the periphery that normally participate in maintenance of glucose homeostasis on a minute-to-minute basis throughout lifetime. Reinstatement of leptin sufficiency in the hypothalamus by either systemic or central injections, or its provision selectively in the hypothalamus with the aid of gene therapy extinguished hyperglycemia and normalized blood glucose stably during the entire course of treatment in a variety of animal models of diabetes type 1 and 2. In follow-up clinical trials, twice daily leptin treatment in leptinopenic and insulinopenic type 1 diabetics and leptinopenic and hyperinsulinemic type 2 diabetics with congenital lipodystrophy or acquired lipoatrophy normalized blood glucose without any discernible adverse effects during the extended course of treatment. Taken together, these findings have amply endorsed the efficacy of leptin therapy to restore glucose homeostasis in insulin-deficient as well as hyperinsulinemic diabetic patients. Consequently, restoration of optimal hypothalmic signaling to reinstate glucose homeostasis with leptin is a highly suitable new therapeutic strategy to ameliorate diabetes type 1 and 2 for the lifetime and to replace the currently in vogue insulin monotherapy. In view of the relentless challenges posed by the worldwide epidemic of diabetes and soaring treatment costs, taken together with the well-known shortcomings of therapies based on restoring insulin signaling, it is highly critical and timely to undertake new clinical trials that ascertain appropriate dosage and route of leptin delivery to the hypothalamus capable of safely sustaining stable glycemia for lifetime.
    Language English
    Publishing date 2013-10-28
    Publishing country India
    Document type Journal Article ; Review
    ZDB-ID 2600211-5
    ISSN 2230-9500 ; 2230-8210
    ISSN (online) 2230-9500
    ISSN 2230-8210
    DOI 10.4103/2230-8210.119496
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A case for new therapy for diabetes, is it leptin?

    Satya P Kalra

    Indian Journal of Endocrinology and Metabolism, Vol 16, Iss 9, Pp 525-

    2012  Volume 528

    Keywords Diseases of the endocrine glands. Clinical endocrinology ; RC648-665 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Endocrine Society of India
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Should leptin replace insulin as a lifetime monotherapy for diabetes type 1 and 2?

    Satya P Kalra

    Indian Journal of Endocrinology and Metabolism, Vol 17, Iss 7, Pp 23-

    2013  Volume 24

    Abstract: Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency ... ...

    Abstract Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency disrupts the relay of hypothalamic regulatory information along three descending pathways to the organs in the periphery that normally participate in maintenance of glucose homeostasis on a minute-to-minute basis throughout lifetime. Reinstatement of leptin sufficiency in the hypothalamus by either systemic or central injections, or its provision selectively in the hypothalamus with the aid of gene therapy extinguished hyperglycemia and normalized blood glucose stably during the entire course of treatment in a variety of animal models of diabetes type 1 and 2. In follow-up clinical trials, twice daily leptin treatment in leptinopenic and insulinopenic type 1 diabetics and leptinopenic and hyperinsulinemic type 2 diabetics with congenital lipodystrophy or acquired lipoatrophy normalized blood glucose without any discernible adverse effects during the extended course of treatment. Taken together, these findings have amply endorsed the efficacy of leptin therapy to restore glucose homeostasis in insulin-deficient as well as hyperinsulinemic diabetic patients. Consequently, restoration of optimal hypothalmic signaling to reinstate glucose homeostasis with leptin is a highly suitable new therapeutic strategy to ameliorate diabetes type 1 and 2 for the lifetime and to replace the currently in vogue insulin monotherapy. In view of the relentless challenges posed by the worldwide epidemic of diabetes and soaring treatment costs, taken together with the well-known shortcomings of therapies based on restoring insulin signaling, it is highly critical and timely to undertake new clinical trials that ascertain appropriate dosage and route of leptin delivery to the hypothalamus capable of safely sustaining stable glycemia for lifetime.
    Keywords Brain ; diabetes ; leptin ; Diseases of the endocrine glands. Clinical endocrinology ; RC648-665 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R
    Subject code 630
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Endocrine Society of India
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation.

    Kalra, Satya P

    Peptides

    2009  Volume 30, Issue 10, Page(s) 1957–1963

    Abstract: Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In ... ...

    Abstract Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs--liver, skeletal muscle and brown adipose tissue--to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans.
    MeSH term(s) Animals ; Appetite Regulation/drug effects ; Appetite Regulation/physiology ; Body Weight/drug effects ; Diabetes Mellitus, Type 1/physiopathology ; Diabetes Mellitus, Type 1/therapy ; Diabetes Mellitus, Type 2/etiology ; Diabetes Mellitus, Type 2/physiopathology ; Diabetes Mellitus, Type 2/therapy ; Glucose/metabolism ; Humans ; Hypothalamus/physiology ; Insulin/metabolism ; Leptin/genetics ; Leptin/metabolism ; Leptin/pharmacology ; Obesity/complications ; Obesity/physiopathology ; Signal Transduction/physiology
    Chemical Substances Insulin ; Leptin ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2009-08-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 769028-9
    ISSN 1873-5169 ; 0196-9781
    ISSN (online) 1873-5169
    ISSN 0196-9781
    DOI 10.1016/j.peptides.2009.07.021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Disruption in the leptin-NPY link underlies the pandemic of diabetes and metabolic syndrome: new therapeutic approaches.

    Kalra, Satya P

    Nutrition (Burbank, Los Angeles County, Calif.)

    2008  Volume 24, Issue 9, Page(s) 820–826

    Abstract: Multidisciplinary research from my and my colleagues' laboratory has shown that disruption at various levels of leptin signaling to the interactive hypothalamic network of neuropeptide Y (NPY) and cohorts contributes to the antecedent pathophysiologic ... ...

    Abstract Multidisciplinary research from my and my colleagues' laboratory has shown that disruption at various levels of leptin signaling to the interactive hypothalamic network of neuropeptide Y (NPY) and cohorts contributes to the antecedent pathophysiologic sequelae of the disease cluster of the metabolic syndrome. Disruptions in NPY signaling due to high or low abundance of NPY and cognate receptors dysregulate the homeostatic milieu to promote hyperinsulinemia, hyperglycemia, fat accrual, and overt diabetes. Hyperleptinemia induced by consumption of energy-rich diets inhibits leptin transport across the blood-brain barrier and thereby produces leptin insufficiency in the hypothalamus. Sustained leptin insufficiency results in loss of hypothalamic restraint on pancreatic insulin secretion and diminished glucose metabolism and energy expenditure. This chain of events culminates in hyperinsulinemia, hyperglycemia, and diabetes. Our recent studies have shown that increasing the supply of leptin centrally by gene therapy reinstates the restraint on hypothalamic NPY signaling and ameliorates diabetes and the attendant disease cluster of the metabolic syndrome. Thus, newer therapies that would enhance leptin transport across the blood-brain barrier in a timely manner or reinstate leptin restraint on NPY signaling through central leptin gene therapy or pharmacologically with leptin mimetics are likely to curtail the pathophysiologic sequelae of diabetes and related ailments of the metabolic syndrome.
    MeSH term(s) Animals ; Diabetes Mellitus/metabolism ; Diabetes Mellitus/therapy ; Hypothalamus/physiopathology ; Leptin/metabolism ; Metabolic Syndrome/metabolism ; Metabolic Syndrome/therapy ; Mice ; Neuropeptide Y/metabolism ; Rats
    Chemical Substances Leptin ; Neuropeptide Y
    Language English
    Publishing date 2008-08-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 639259-3
    ISSN 1873-1244 ; 0899-9007
    ISSN (online) 1873-1244
    ISSN 0899-9007
    DOI 10.1016/j.nut.2008.06.023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Central leptin insufficiency syndrome: an interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions.

    Kalra, Satya P

    Peptides

    2007  Volume 29, Issue 1, Page(s) 127–138

    Abstract: This review critically reappraises recent scientific evidence concerning central leptin insufficiency versus leptin resistance formulations to explain metabolic and neural disorders resulting from subnormal or defective leptin signaling in various sites ... ...

    Abstract This review critically reappraises recent scientific evidence concerning central leptin insufficiency versus leptin resistance formulations to explain metabolic and neural disorders resulting from subnormal or defective leptin signaling in various sites in the brain. Research at various fronts to unravel the complexities of the neurobiology of leptin is surveyed to provide a comprehensive account of the neural and metabolic effects of environmentally imposed fluctuations in leptin availability at brain sites and the outcome of newer technology to restore leptin signaling in a site-specific manner. The cumulative new knowledge favors a unified central leptin insufficiency syndrome over the, in vogue, central resistance hypothesis to explain the global adverse impact of deficient leptin signaling in the brain. Furthermore, the leptin insufficiency syndrome delineates a novel role of leptin in the hypothalamus in restraining rhythmic pancreatic insulin secretion while concomitantly enhancing glucose metabolism and non-shivering thermogenic energy expenditure, sequelae that would otherwise promote fat accrual to store excess energy resulting from consumption of energy-enriched diets. A concerted effort should now focus on development of newer technologies for delivery of leptin or leptin mimetics to specifically target neural pathways for remediation of diverse ailments encompassing the central leptin insufficiency syndrome.
    MeSH term(s) Animals ; Humans ; Leptin/deficiency ; Leptin/metabolism ; Metabolic Diseases/etiology ; Metabolic Diseases/metabolism ; Metabolic Diseases/therapy ; Nervous System Diseases/etiology ; Nervous System Diseases/metabolism ; Nervous System Diseases/therapy ; Obesity/etiology ; Obesity/metabolism ; Obesity/therapy ; Syndrome
    Chemical Substances Leptin
    Language English
    Publishing date 2007-10-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 769028-9
    ISSN 1873-5169 ; 0196-9781
    ISSN (online) 1873-5169
    ISSN 0196-9781
    DOI 10.1016/j.peptides.2007.10.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Global life-long health benefits of repression of hypothalamic NPY system by central leptin gene therapy.

    Kalra, Satya P

    Current topics in medicinal chemistry

    2007  Volume 7, Issue 17, Page(s) 1675–1681

    Abstract: A minute-to-minute crosstalk between the hypothalamic neuropeptide Y (NPY) network and the hormone leptin is essential for energy homeostasis. Leptin insufficiency i.e. lack of leptin restraint due to genetic and environmental factors on the hypothalamic ...

    Abstract A minute-to-minute crosstalk between the hypothalamic neuropeptide Y (NPY) network and the hormone leptin is essential for energy homeostasis. Leptin insufficiency i.e. lack of leptin restraint due to genetic and environmental factors on the hypothalamic NPY system confers obesity, a cluster of metabolic afflictions and shorter lifespan. A state-of-the-art gene transfer technology using recombinant adeno-associated viral vector to overcome hypothalamic leptin insufficiency was employed in rodent models of obesity, metabolic syndrome and shorter lifespan. Our findings show that life-long tonic repression of NPY system with a stable increase in leptin availability in the hypothalamus prevented the age-related and high fat-diet-induced obesity, hyperinsulinemia and diabetes and extended lifespan. Additional health benefits include increased energy expenditure and normalization of neuroendocrine control on reproduction, and promotion of brain and bone growth. We propose that central leptin gene therapy or novel long-acting leptin mimetics should be tested clinically to decelerate the worldwide epidemic of obesity, diabetes and shortened lifespan.
    MeSH term(s) Animals ; Genetic Therapy/methods ; Humans ; Hypothalamus/metabolism ; Insurance Benefits ; Leptin/biosynthesis ; Leptin/genetics ; Leptin/metabolism ; Life Expectancy ; Neuropeptide Y/antagonists & inhibitors ; Neuropeptide Y/metabolism ; Obesity/prevention & control
    Chemical Substances Leptin ; Neuropeptide Y
    Language English
    Publishing date 2007-10-15
    Publishing country United Arab Emirates
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2064823-6
    ISSN 1873-4294 ; 1568-0266
    ISSN (online) 1873-4294
    ISSN 1568-0266
    DOI 10.2174/156802607782340993
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Neuroendocrine control of energy homeostasis: update on new insights.

    Kalra, Satya P / Kalra, Pushpa S

    Progress in brain research

    2010  Volume 181, Page(s) 17–33

    Abstract: Recent upsurge in research has uncovered distinct circuitries that regulate appetite, energy expenditure and fat accrual under the supervision of hormonal feedback signalling of adipocyte leptin and gastric ghrelin in the hypothalamic integration of ... ...

    Abstract Recent upsurge in research has uncovered distinct circuitries that regulate appetite, energy expenditure and fat accrual under the supervision of hormonal feedback signalling of adipocyte leptin and gastric ghrelin in the hypothalamic integration of energy homeostasis. A host of messenger molecules of diverse chemical composition and origin mediate the crosstalk between the three circuitries. Leptin is now recognized as the mandatory afferent signal in maintenance of weight homeostasis. Leptin insufficiency in the hypothalamus due to diminished transport of leptin across the blood-brain barrier (BBB) imposed by environmental causes, such as consumption of energy-enriched diets and diminished energy expenditure, orchestrates unregulated fat accrual and the attendant disease cluster of metabolic syndrome. Bioavailability of leptin selectively in the hypothalamic targets with the aid of gene therapy successfully averted the environmentally induced metabolic afflictions and normalized lifespan. Thus, sustenance of optimal sufficiency in leptin signalling solely in the hypothalamus is a novel strategy to combat the worldwide epidemic of obesity and metabolic syndrome.
    MeSH term(s) Animals ; Appetite/physiology ; Body Weight ; Energy Metabolism/physiology ; Ghrelin/metabolism ; Homeostasis/physiology ; Humans ; Hypothalamus/anatomy & histology ; Hypothalamus/metabolism ; Leptin/genetics ; Leptin/metabolism ; Metabolic Syndrome/physiopathology ; Neurosecretory Systems/physiology ; Obesity/physiopathology ; Signal Transduction/physiology
    Chemical Substances Ghrelin ; Leptin
    Language English
    Publishing date 2010
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ISSN 1875-7855 ; 0079-6123
    ISSN (online) 1875-7855
    ISSN 0079-6123
    DOI 10.1016/S0079-6123(08)81002-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: To subjugate NPY is to improve the quality of life and live longer.

    Kalra, Satya P / Kalra, Pushpa S

    Peptides

    2007  Volume 28, Issue 2, Page(s) 413–418

    Abstract: The interactive network of neuropeptide Y (NPY) and cohorts is necessary for integrating the hypothalamic regulation of appetite and energy expenditure with the endocrine and neuroendocrine systems on a daily basis. Genetic and environmental factors that ...

    Abstract The interactive network of neuropeptide Y (NPY) and cohorts is necessary for integrating the hypothalamic regulation of appetite and energy expenditure with the endocrine and neuroendocrine systems on a daily basis. Genetic and environmental factors that produce an insufficiency of leptin restraint on NPY and cognate receptors deregulate the homeostasis to engender various life-threatening risk factors. Recent studies from our laboratory show that neurotherapy consisting of a single central administration of recombinant adeno-associated virus vector encoding the leptin gene can repress the hypothalamic NPY system for the lifetime of rodents. A major benefit of this stable tonic restraint is deceleration of pathophysiologic sequalae that shorten life span. These include suppression of weight gain, fat accumulation, circulating adipokines, amelioration of major symptoms of metabolic syndrome, improved reproduction and bone health. Thus, sustained repression of NPY signaling in the hypothalamus by leptin transgene expression can improve the quality of life and extend longevity.
    MeSH term(s) Appetite ; Genetic Therapy ; Humans ; Hypothalamus/physiology ; Leptin/genetics ; Neuropeptide Y/antagonists & inhibitors ; Neuropeptide Y/physiology ; Quality of Life
    Chemical Substances Leptin ; Neuropeptide Y
    Language English
    Publishing date 2007-01-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 769028-9
    ISSN 1873-5169 ; 0196-9781
    ISSN (online) 1873-5169
    ISSN 0196-9781
    DOI 10.1016/j.peptides.2006.08.039
    Database MEDical Literature Analysis and Retrieval System OnLINE

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