Beyond Insulin; The other hormones of the Islets of Langerhans
Mar 10, 2023
While I am a clinical trialist that runs several industry and govt sponsored clinical
trials all funds from these trials are paid directly to the Ochsner medical foundation.
• Nothing presented during this presentation has any relationship to any of the
therapeutic medications nor devices in any of my ongoing or completed clinical
trials.
• There are no personal nor family related/affiliated disclosures of any relevance nor
bearing to any of the material presented here.
Welcome message from author
Of the Islets of Langerhans it can truly be said that “never has so much been owed by so many to so few”; that 1% of the pancreatic mass should never be taken for granted. There remains so much to learn of it though it has already provided clinical medicine so much thus far over the last century.
Transcript
Beyond Insulin; The other hormones of the Islets of LangerhansDisclosures Statement • While I am a clinical trialist that runs several industry and govt sponsored clinical
trials all funds from these trials are paid directly to the Ochsner medical foundation.
• Nothing presented during this presentation has any relationship to any of the therapeutic medications nor devices in any of my ongoing or completed clinical trials.
• There are no personal nor family related/affiliated disclosures of any relevance nor bearing to any of the material presented here.
• 1893; The term “islets of Langerhans” was introduced in by Edouard Laguesse, who observed them in the human pancreas and (with remarkable foresight) suggested that they may produce internal secretions that regulate glycemia.
Paul Langerhans
Edouard Laguesse
stromal cells (fibroblasts), vascular cells (endothelial cells, pericytes), immune cells (granulocytes, lymphocytes, macrophages, dendritic cells) and neural cells.
• The islets contain at least 5 distinct endocrine cell types each with distinctive hormonal products.
• The hormonal products have endocrine, autocrine and paracrine effects and interactions.
Stained islet H and E pancreas
Alpha cell stained islet
Beta cell stained islet
•Beta cells producing insulin, proinsulin, C- peptide and amylin (≈70%)
•Delta cells producing somatostatin (<10%)
•Epsilon cells producing ghrelin (<1%)
•PP cells (gamma cells or F cells) producing pancreatic polypeptide (<5%)
- Glucose/Insulin: activates beta cells and inhibits alpha cells
- Glycogen/Glucagon: activates alpha cells which activates beta cells and delta cells
- Somatostatin: inhibits alpha cells and beta cells
The hyperglycemic effect of glucagon was described
as early as 1922 by Kimball and Murlin
who discovered a hyperglycemic factor in pancreatic
extracts and called this factor “the glucose agonist", hence
the name glucagon.
In the 1950s glucagon was purified and crystallized at Eli
Lilly and Co.,
and shortly after, the amino acid sequence of the peptide
was determined.
hypoglycemia, amino acids and the gut hormone
glucose-dependent insulinotropic peptide (GIP),
release.
zinc and possibly amylin. Glucagon may regulate its
own secretion indirectly via stimulatory effect on beta
cells to secrete insulin
Tissue specific processing of proglucagon. In the pancreas proglucagon is
processed into glucagon, glicentin-related pancreatic polypeptide (GRPP),
intervening peptide 1 (IP1), and major proglucagon fragment (MPGF) by
the processing enzyme prohormone convertase 2 (PC2). In the intestine
and in the brain proglucagon is processed by prohormone convertase 1/3
(PC1/3) into glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2
(GLP-2), oxyntomodulin, intervening peptide 2 (IP2), and glicentin.
The Beta Cell; Proinsulin, C-peptide, Insulin, Amylin, Proamylin (aka pro-islet amyloid polypeptide)
• Proinsulin; 86aa polypeptide first sequenced 1967 by Donald Steiner.
• C-peptide; 31 aa polypeptide first sequenced 1967 by Donald Steiner
• Insulin; 51 aa heterodimer polypeptide (21 aa A chain and 30 aa B chain) first sequenced by Fred Sanger ; 1951
• Amylin aka islet amyloid polypeptide (IAPP) is a 37 aa polypeptide which is co-secreted with insulin from the beta cell in a 1:100 typical molar ratio. It was first isolated and sequenced by a basic research team @ Oxford University in 1987.
• Its pro hormone; Proamylin aka pro- islet amyloid polypeptide or pro-islet protein) is a 67 aa polypeptide product formed after rapid post translational cleavage of a 22 aa signal peptide from the 89 aa pre-pro product.
AM833, a Long Acting Amylin Analogue
BZ043, a novel long-acting amylin analog
Cagrilintide, a Long-Acting Amylin Analogue
NNC0174-0839 (Novo Nordisk) is a dual-acting amylin analogue with agonistic effects on the amylin receptor as well as the calcitonin receptor.
• Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one consisting of 14 aas the other consisting of 28 aas.
• It was first discovered and sequenced in 1973 by Roger Guillemen
The Delta cell; Somatostatin (aka the Growth hormone inhibiting hormone)
The PP, Gamma or F cells; Pancreatic Polypeptide.
• M Kojima and associated discovered and sequenced Ghrelin in 1999 as a 28 aa polypeptide extracted from rat stomachs.
• The Ghrelin gene produces mRNA which has four exons. Five products arise: A 117 aa preproghrelin which is homologous to promotilin. It is cleaved to produce proghrelin which is then cleaved to produce an unacylated 28-aa ghrelin and an acylated C-ghrelin. Obestatin is presumed to be cleaved from C-ghrelin.
• Ghrelin cells are found mainly in the stomach and duodenum, but also in the jejunum, lungs, pancreatic islets, gonads, adrenal cortex, placenta, and kidney. It has also been shown that ghrelin is produced locally in the brain.
Epsilon Cells; Ghrelin aka lenomorelin
Namorelin (ONO-7643, RC-1291, ST-1291)
Anamorelin is an orally active, centrally- penetrant, selective Ghrelin agonist with appetite-enhancing and anabolic effects (approved in Japan for cancer related cachexia).
Macimorelin (aka Macrilen) for diagnostics of growth hormone deficiency
Roles in therapeutics; for cachexia (including cancer cachexia), anorexic states, wasting syndrome
Epsilon Cells; Ghrelin
Islet Neogenesis–Associated Protein
stimulation of insulin secretion, islet regeneration, improve islet survival and function and angiogenesis both in rodent and human islets. In addition to increasing functionality and survival of isolated rat islets, INGAP has been shown to increase viability of islet allografts post-transplantation.
Other endocrine cells of the islets;
GLP-1/glucagon; MEDI0382, SAR425899, Cotadutide.(Astra Zeneca) Beyond diabetes and obesity therapeutics some of these agents are showing exciting potential in NASH, NAFLD and liver regeneration clinical therapeutics.
GLP-1/GIP; the so called twincretins; RG7697 (also known as NNC0090-2746), LY3298176 (aka tirzepatide; Lilly) used in diabetes and obesity therapeutics. Some of these agents are also showing promise for potential neuroprotective effects in animal models of brain injury, Parkinson and Alzheimer disease.
GLP-1/CCK; C2816
GLP-1/xenin or GIP/xenin;
HM15211, a long-acting tri-agonist peptide conjugated to the human aglycosylate Fc fragment,
Another tri-agonist, MAR423
To overcome the inherent GIP resistance in Type 2 diabetes condition, a triple agonist peptide was engineered by combining a previously characterized exendin-4/gastrin dual-agonist with xenin-8-Gln.
PYY, GLP-1, and/or OXM coadministration has also shown promise in small preclinical and clinical trial settings and so attempts to develop tri-agonist molecules in this regard are also actively underway.
• Of the Islets of Langerhans it can truly be said that “never has so much been owed by so many to so few”; that 1% of the pancreatic mass should never be taken for granted. There remains so much to learn of it though it has already provided clinical medicine so much thus far over the last century.
Bibliography and References
• An Autonomous Cannabinoid System in Islets of Langerhans. Aseer KR, Egan JM. Front Endocrinol (Lausanne). 2021 Jul 5;12:699661. doi: 10.3389/fendo.2021.699661. eCollection 2021.
• Glucagon Physiology. Iben Rix, Christina Nexøe-Larsen, Natasha C Bergmann, Asger Lund, and Filip K Knop. www.endotext.org, 2019.
• The Human Islet: Mini-Organ With Mega-Impact. John T. Walker, Diane C. Saunders, Marcela Brissova, and Alvin C. Powers. Endocrine Reviews, 2021, Vol. XX, No. XX, 1–53
• Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes? Lorenzo PI, Cobo-Vuilleumier N, Martín-Vázquez E, López-Noriega L, Gauthier BR.Int J Mol Sci. 2021 Apr 19;22(8):4239. doi: 10.3390/ijms22084239.
• State-of-the-art microscopy to understand islets of Langerhans: what to expect next? de Boer P, Giepmans BN. Immunol Cell Biol. 2021 May;99(5):509-520. doi: 10.1111/imcb.12450.
• Deciphering the Complex Communication Networks That Orchestrate Pancreatic Islet Function. Weitz J, Menegaz D, Caicedo A. Diabetes. 2021 Jan;70(1):17-26. doi: 10.2337/dbi19-0033.
Questions???, Comments???
trials all funds from these trials are paid directly to the Ochsner medical foundation.
• Nothing presented during this presentation has any relationship to any of the therapeutic medications nor devices in any of my ongoing or completed clinical trials.
• There are no personal nor family related/affiliated disclosures of any relevance nor bearing to any of the material presented here.
• 1893; The term “islets of Langerhans” was introduced in by Edouard Laguesse, who observed them in the human pancreas and (with remarkable foresight) suggested that they may produce internal secretions that regulate glycemia.
Paul Langerhans
Edouard Laguesse
stromal cells (fibroblasts), vascular cells (endothelial cells, pericytes), immune cells (granulocytes, lymphocytes, macrophages, dendritic cells) and neural cells.
• The islets contain at least 5 distinct endocrine cell types each with distinctive hormonal products.
• The hormonal products have endocrine, autocrine and paracrine effects and interactions.
Stained islet H and E pancreas
Alpha cell stained islet
Beta cell stained islet
•Beta cells producing insulin, proinsulin, C- peptide and amylin (≈70%)
•Delta cells producing somatostatin (<10%)
•Epsilon cells producing ghrelin (<1%)
•PP cells (gamma cells or F cells) producing pancreatic polypeptide (<5%)
- Glucose/Insulin: activates beta cells and inhibits alpha cells
- Glycogen/Glucagon: activates alpha cells which activates beta cells and delta cells
- Somatostatin: inhibits alpha cells and beta cells
The hyperglycemic effect of glucagon was described
as early as 1922 by Kimball and Murlin
who discovered a hyperglycemic factor in pancreatic
extracts and called this factor “the glucose agonist", hence
the name glucagon.
In the 1950s glucagon was purified and crystallized at Eli
Lilly and Co.,
and shortly after, the amino acid sequence of the peptide
was determined.
hypoglycemia, amino acids and the gut hormone
glucose-dependent insulinotropic peptide (GIP),
release.
zinc and possibly amylin. Glucagon may regulate its
own secretion indirectly via stimulatory effect on beta
cells to secrete insulin
Tissue specific processing of proglucagon. In the pancreas proglucagon is
processed into glucagon, glicentin-related pancreatic polypeptide (GRPP),
intervening peptide 1 (IP1), and major proglucagon fragment (MPGF) by
the processing enzyme prohormone convertase 2 (PC2). In the intestine
and in the brain proglucagon is processed by prohormone convertase 1/3
(PC1/3) into glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2
(GLP-2), oxyntomodulin, intervening peptide 2 (IP2), and glicentin.
The Beta Cell; Proinsulin, C-peptide, Insulin, Amylin, Proamylin (aka pro-islet amyloid polypeptide)
• Proinsulin; 86aa polypeptide first sequenced 1967 by Donald Steiner.
• C-peptide; 31 aa polypeptide first sequenced 1967 by Donald Steiner
• Insulin; 51 aa heterodimer polypeptide (21 aa A chain and 30 aa B chain) first sequenced by Fred Sanger ; 1951
• Amylin aka islet amyloid polypeptide (IAPP) is a 37 aa polypeptide which is co-secreted with insulin from the beta cell in a 1:100 typical molar ratio. It was first isolated and sequenced by a basic research team @ Oxford University in 1987.
• Its pro hormone; Proamylin aka pro- islet amyloid polypeptide or pro-islet protein) is a 67 aa polypeptide product formed after rapid post translational cleavage of a 22 aa signal peptide from the 89 aa pre-pro product.
AM833, a Long Acting Amylin Analogue
BZ043, a novel long-acting amylin analog
Cagrilintide, a Long-Acting Amylin Analogue
NNC0174-0839 (Novo Nordisk) is a dual-acting amylin analogue with agonistic effects on the amylin receptor as well as the calcitonin receptor.
• Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one consisting of 14 aas the other consisting of 28 aas.
• It was first discovered and sequenced in 1973 by Roger Guillemen
The Delta cell; Somatostatin (aka the Growth hormone inhibiting hormone)
The PP, Gamma or F cells; Pancreatic Polypeptide.
• M Kojima and associated discovered and sequenced Ghrelin in 1999 as a 28 aa polypeptide extracted from rat stomachs.
• The Ghrelin gene produces mRNA which has four exons. Five products arise: A 117 aa preproghrelin which is homologous to promotilin. It is cleaved to produce proghrelin which is then cleaved to produce an unacylated 28-aa ghrelin and an acylated C-ghrelin. Obestatin is presumed to be cleaved from C-ghrelin.
• Ghrelin cells are found mainly in the stomach and duodenum, but also in the jejunum, lungs, pancreatic islets, gonads, adrenal cortex, placenta, and kidney. It has also been shown that ghrelin is produced locally in the brain.
Epsilon Cells; Ghrelin aka lenomorelin
Namorelin (ONO-7643, RC-1291, ST-1291)
Anamorelin is an orally active, centrally- penetrant, selective Ghrelin agonist with appetite-enhancing and anabolic effects (approved in Japan for cancer related cachexia).
Macimorelin (aka Macrilen) for diagnostics of growth hormone deficiency
Roles in therapeutics; for cachexia (including cancer cachexia), anorexic states, wasting syndrome
Epsilon Cells; Ghrelin
Islet Neogenesis–Associated Protein
stimulation of insulin secretion, islet regeneration, improve islet survival and function and angiogenesis both in rodent and human islets. In addition to increasing functionality and survival of isolated rat islets, INGAP has been shown to increase viability of islet allografts post-transplantation.
Other endocrine cells of the islets;
GLP-1/glucagon; MEDI0382, SAR425899, Cotadutide.(Astra Zeneca) Beyond diabetes and obesity therapeutics some of these agents are showing exciting potential in NASH, NAFLD and liver regeneration clinical therapeutics.
GLP-1/GIP; the so called twincretins; RG7697 (also known as NNC0090-2746), LY3298176 (aka tirzepatide; Lilly) used in diabetes and obesity therapeutics. Some of these agents are also showing promise for potential neuroprotective effects in animal models of brain injury, Parkinson and Alzheimer disease.
GLP-1/CCK; C2816
GLP-1/xenin or GIP/xenin;
HM15211, a long-acting tri-agonist peptide conjugated to the human aglycosylate Fc fragment,
Another tri-agonist, MAR423
To overcome the inherent GIP resistance in Type 2 diabetes condition, a triple agonist peptide was engineered by combining a previously characterized exendin-4/gastrin dual-agonist with xenin-8-Gln.
PYY, GLP-1, and/or OXM coadministration has also shown promise in small preclinical and clinical trial settings and so attempts to develop tri-agonist molecules in this regard are also actively underway.
• Of the Islets of Langerhans it can truly be said that “never has so much been owed by so many to so few”; that 1% of the pancreatic mass should never be taken for granted. There remains so much to learn of it though it has already provided clinical medicine so much thus far over the last century.
Bibliography and References
• An Autonomous Cannabinoid System in Islets of Langerhans. Aseer KR, Egan JM. Front Endocrinol (Lausanne). 2021 Jul 5;12:699661. doi: 10.3389/fendo.2021.699661. eCollection 2021.
• Glucagon Physiology. Iben Rix, Christina Nexøe-Larsen, Natasha C Bergmann, Asger Lund, and Filip K Knop. www.endotext.org, 2019.
• The Human Islet: Mini-Organ With Mega-Impact. John T. Walker, Diane C. Saunders, Marcela Brissova, and Alvin C. Powers. Endocrine Reviews, 2021, Vol. XX, No. XX, 1–53
• Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes? Lorenzo PI, Cobo-Vuilleumier N, Martín-Vázquez E, López-Noriega L, Gauthier BR.Int J Mol Sci. 2021 Apr 19;22(8):4239. doi: 10.3390/ijms22084239.
• State-of-the-art microscopy to understand islets of Langerhans: what to expect next? de Boer P, Giepmans BN. Immunol Cell Biol. 2021 May;99(5):509-520. doi: 10.1111/imcb.12450.
• Deciphering the Complex Communication Networks That Orchestrate Pancreatic Islet Function. Weitz J, Menegaz D, Caicedo A. Diabetes. 2021 Jan;70(1):17-26. doi: 10.2337/dbi19-0033.
Questions???, Comments???
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