Studies on Islet Hormone Secretion in Studies on Islet Hormone Secretion in MODY1: RW Pedigree with Q268X MODY1: RW Pedigree with Q268X

Mutation in HNF-4Mutation in HNF-4 Gene Gene

Three groups of 4 to 7 subjects each:Three groups of 4 to 7 subjects each:No mutation identified, not diabetic: No mutation identified, not diabetic: ND (–)ND (–)

Mutation identified, not diabetic: Mutation identified, not diabetic: ND (+)ND (+)

Mutation identified, diabetic: Mutation identified, diabetic: D (+)D (+)

MODY1 (RW Pedigree): Plasma C-Peptide Levels MODY1 (RW Pedigree): Plasma C-Peptide Levels in Response to L-Arginine Infused IV Alone and in Response to L-Arginine Infused IV Alone and

Again During Hyperglycemic ClampAgain During Hyperglycemic Clamp

MODY1 (RW Pedigree): Insulin Secretion Rates MODY1 (RW Pedigree): Insulin Secretion Rates (ISR) by Deconvolution of Plasma (ISR) by Deconvolution of Plasma

C-Peptide Levels During IV L-Arginine InfusionC-Peptide Levels During IV L-Arginine Infusion

MODY1 (RW Pedigree): Plasma Amylin Levels in MODY1 (RW Pedigree): Plasma Amylin Levels in Response to L-Arginine Infused IV Alone and Response to L-Arginine Infused IV Alone and

Again During Hyperglycemic ClampAgain During Hyperglycemic Clamp

MODY1 (RW Pedigree): Plasma Glucagon Response MODY1 (RW Pedigree): Plasma Glucagon Response Areas (AUC) During IV Infusion of L-ArginineAreas (AUC) During IV Infusion of L-Arginine

MODY1 (RW Pedigree): MODY1 (RW Pedigree): Plasma Pancreatic Polypeptide Response Areas Plasma Pancreatic Polypeptide Response Areas

(AUC) to Insulin-Induced Hypoglycemia(AUC) to Insulin-Induced Hypoglycemia

Conclusions Regarding Pancreatic Islet Conclusions Regarding Pancreatic Islet Function in MODY1 (HNF-4Function in MODY1 (HNF-4Mutation) Mutation) [1/2][1/2]

Nondiabetic as well as diabetic Nondiabetic as well as diabetic subjects have a defect insubjects have a defect in insulin secretion in response to insulin secretion in response to

administered arginine as well as to administered arginine as well as to glucoseglucose

glucagon secretion in response to glucagon secretion in response to administered arginineadministered arginine

pancreatic polypeptide (PP) secretion in pancreatic polypeptide (PP) secretion in response to insulin-induced hypoglycemiaresponse to insulin-induced hypoglycemia

Conclusions Regarding Pancreatic Islet Conclusions Regarding Pancreatic Islet Function in MODY1 (HNF-4Function in MODY1 (HNF-4Mutation) Mutation) [2/2][2/2]

The secretory defect in the three islet-The secretory defect in the three islet-cell types (cell types (-, -, - and PP-cells) may be - and PP-cells) may be at a common step in signal transduction, orat a common step in signal transduction, or

due to a decrease in the mass of the due to a decrease in the mass of the respective cell type, orrespective cell type, or

signal transduction and cell mass defectssignal transduction and cell mass defects

Course of the Insulin-Secretory Defect Course of the Insulin-Secretory Defect in MODY1 (HNF-4in MODY1 (HNF-4MutationMutation

Progressive decrease in insulin Progressive decrease in insulin secretion at a rate of 1-4% per year secretion at a rate of 1-4% per year over a period of 3 decades over a period of 3 decades (observed in the RW Pedigree)(observed in the RW Pedigree)

Pathogenesis of Pathogenesis of MODY1 (HNF-4MODY1 (HNF-4MutationMutation

HNF-4HNF-4 protein protein is a member of the steroid hormone receptor is a member of the steroid hormone receptor

superfamily of nuclear transcription factorssuperfamily of nuclear transcription factors

plays a role in tissue-specific regulation of plays a role in tissue-specific regulation of expression of multiple genes in the liver, expression of multiple genes in the liver, pancreas, kidney, intestine, including the pancreas, kidney, intestine, including the genes that regulate glucose transport and genes that regulate glucose transport and glycolysis glycolysis (Stoffel & Duncan) (Stoffel & Duncan)

Pathogenesis of Pathogenesis of -cell Dysfunction -cell Dysfunction in MODY1 (HNF-4in MODY1 (HNF-4MutationMutation

Defective insulin secretion associated Defective insulin secretion associated with HNF-4with HNF-4 mutation is linked to mutation is linked to impaired mitochondrial oxidation impaired mitochondrial oxidation (Wang (Wang et alet al))

HNF-4HNF-4 regulates gene expression regulates gene expression in islet in islet -cells by influencing the function -cells by influencing the function of the HNF-1of the HNF-1 protein protein (Wang (Wang et alet al)),, and and vice versavice versa (Thomas (Thomas et alet al; Hanson ; Hanson et alet al))

The The -Cell & MODY-Related Proteins-Cell & MODY-Related Proteins

Hepatocyte Dysfunction Hepatocyte Dysfunction Causing Plasma Lipid Changes in Causing Plasma Lipid Changes in

MODY1 (HNF-4MODY1 (HNF-4MutationMutation

HNF-4HNF-4 is essential in controlling is essential in controlling transcription of many genes involved in transcription of many genes involved in lipoprotein metabolism in the liverlipoprotein metabolism in the liver

In prediabetic and diabetic MODY1 In prediabetic and diabetic MODY1 subjects, HNF-4subjects, HNF-4 mutation leads to mutation leads to hepatocyte secretory defects in hepatocyte secretory defects in lipoproteins, resulting in decreased lipoproteins, resulting in decreased serum levels of triglycerides, lipoprotein serum levels of triglycerides, lipoprotein (a), and apolipoproteins A-II and C-III(a), and apolipoproteins A-II and C-III

Serum Levels of Lipoprotein (a) and Serum Levels of Lipoprotein (a) and Triglycerides in Subjects with HNF-4 Triglycerides in Subjects with HNF-4 (RW) and (RW) and

other (MODY-X) Mutationsother (MODY-X) Mutations

Clinical Implications of Genetic Clinical Implications of Genetic Heterogeneity of MODY Heterogeneity of MODY [1/2][1/2]

MODY1 and MODY3MODY1 and MODY3Progressive clinical course in terms of Progressive clinical course in terms of

hyperglycemia, with increasing treatment hyperglycemia, with increasing treatment requirementsrequirements

Development of microvascular, Development of microvascular, macrovascular and neuropathic macrovascular and neuropathic complications of diabetes in a frequency complications of diabetes in a frequency similar to that seen in type 2 diabetessimilar to that seen in type 2 diabetes

Clinical Implications of Genetic Clinical Implications of Genetic Heterogeneity of MODY Heterogeneity of MODY [2/2][2/2]

MODY2MODY2Mild to moderate elevation in plasma glucose Mild to moderate elevation in plasma glucose

levelslevels

Not progressiveNot progressive

Complications rareComplications rare

Molecular-genetic diagnosis has Molecular-genetic diagnosis has important implications for clinical important implications for clinical management of all MODY subtypesmanagement of all MODY subtypes

Differences in Clinical Parameters Differences in Clinical Parameters Among Diabetic MODY Subtypes Among Diabetic MODY Subtypes [1/2][1/2]

ParameterParameter MODY1 MODY1 MODY2MODY2 MODY3MODY3

Plasma glucosePlasma glucose

FastingFasting Normal toNormal to Mildly Mildly Normal toNormal toseverely severely severely severely

Post-prandial Post-prandial Greatly Greatly Mildly Mildly Greatly Greatly Progression ofProgression of

hyperglycemiahyperglycemia Severe Severe None or mildNone or mild SevereSevere

MicrovascularMicrovascularcomplicationscomplications CommonCommon RareRare CommonCommon

Renal thresholdRenal thresholdfor glucosefor glucose NormalNormal NormalNormal LowLow

Differences in Clinical Parameters Differences in Clinical Parameters Among Diabetic MODY Subtypes Among Diabetic MODY Subtypes [2/2][2/2]

ParameterParameter MODY1MODY1 MODY2MODY2 MODY3MODY3

Sensitivity toSensitivity tosulfonylurea sulfonylurea Normal Normal NormalNormal IncreasedIncreased

TreatmentTreatment Progressive Progressive RareRare ProgressiveProgressiverequirements requirements 1/3 oral agent1/3 oral agent 1/3 oral agent1/3 oral agent

1/3 insulin1/3 insulin 1/3 insulin1/3 insulin PlasmaPlasma Triglycerides Triglycerides Apo M Apo M

lipoproteinslipoproteins Lp (a) Lp (a) Apo AII Apo AII Apo CIII Apo CIII

MODY5 is associated with congenital MODY5 is associated with congenital glomerulocystic, uterine and genitalglomerulocystic, uterine and genital developmental developmental disorders.disorders.

Chronic Complications of Diabetes Chronic Complications of Diabetes in MODYin MODY

Microvascular and neuropathic Microvascular and neuropathic complications as common in MODY1 complications as common in MODY1 and MODY3 as in Type 2 diabetes and MODY3 as in Type 2 diabetes matched for duration and degree of matched for duration and degree of

hyperglycemia hyperglycemia

most likely determined by the degree of most likely determined by the degree of glycemic controlglycemic control

MODY: Clinical StrategiesMODY: Clinical Strategies

Molecular-genetic screening and diagnosis Molecular-genetic screening and diagnosis are feasible for young subjects at risk for are feasible for young subjects at risk for MODY, and have important prognostic MODY, and have important prognostic implications.implications.

Genetically susceptible subjects can be Genetically susceptible subjects can be counseled to have periodic evaluation of counseled to have periodic evaluation of glucose tolerance beginning at a young age.glucose tolerance beginning at a young age.

Attainment of normoglycemia beginning Attainment of normoglycemia beginning at time of appearance of metabolic at time of appearance of metabolic abnormalities can prevent vascular abnormalities can prevent vascular and neuropathic complications.and neuropathic complications.

Estimated Worldwide Prevalence Estimated Worldwide Prevalence of MODYof MODY

2 to 5 % of all diabetic patients2 to 5 % of all diabetic patients

Distribution of MODY SubtypesDistribution of MODY Subtypes

MODY SubtypeMODY Subtype UnitedUnited France France Kingdom Kingdom

MODY1MODY1 5% 5% 0%0%

MODY2MODY2 12% 12% 63% 63%

MODY3MODY3 64% 64% 21% 21%

MODY4MODY4 2% 2% 0%0%

MODY5MODY5 1% 1% 0%0%

MODY“X” MODY“X” (unknown)(unknown) 16% 16% 16% 16%

MODY: Expectations for the FutureMODY: Expectations for the Future

Understanding of the pathophysiology Understanding of the pathophysiology of MODY emerging from molecular-of MODY emerging from molecular-biological and physiological studies biological and physiological studies will lead to new therapeutic approaches will lead to new therapeutic approaches that delay, prevent or correct the that delay, prevent or correct the decline in pancreatic islet decline in pancreatic islet -cell -cell function.function.

MODY could serve as a paradigm for MODY could serve as a paradigm for similar studies in genetically more similar studies in genetically more complex forms of diabetes.complex forms of diabetes.

Potential Future Development of Drugs That Potential Future Development of Drugs That Target HNF-4Target HNF-4 Haplo-Insufficiency Haplo-Insufficiency

In MODY1: In MODY1: Agonist agents specifically acting on the islet Agonist agents specifically acting on the islet --cell, to increase HNF-4cell, to increase HNF-4activity, and improve activity, and improve insulin secretioninsulin secretion

In MODY3: Similar agonist agents to increase In MODY3: Similar agonist agents to increase HNF-1HNF-1activity activity

In non-MODY subjects with dyslipoproteinemia: In non-MODY subjects with dyslipoproteinemia: Antagonist agents selectively acting on the liver Antagonist agents selectively acting on the liver and intestine, to improve lipoprotein metabolismand intestine, to improve lipoprotein metabolism

MODY: Extension to Type 2 Diabetes MODY: Extension to Type 2 Diabetes [1/2][1/2]

Recent evidence suggests that Recent evidence suggests that misregulation of the HNF transcription misregulation of the HNF transcription factor network in pancreatic islets and factor network in pancreatic islets and liver, and particularly HNF-4liver, and particularly HNF-4, may , may contribute to Type 2 diabetes.contribute to Type 2 diabetes.

(Odom DT (Odom DT et al.et al. ScienceScience 2004;303:1378-81; 2004;303:1378-81; Kulkarni RN, Kahn CR. Kulkarni RN, Kahn CR. ScienceScience 2004;303:1311-2.) 2004;303:1311-2.)

MODY: Extension to Type 2 Diabetes MODY: Extension to Type 2 Diabetes [2/2][2/2]

Genetic studies in an Ashkenazi-Jewish Genetic studies in an Ashkenazi-Jewish population (1), and in families resident in population (1), and in families resident in Finland (2) revealed significant haplotype-Finland (2) revealed significant haplotype-tag single nucleotide polymorphisms tag single nucleotide polymorphisms (htSNPs) in the HNF-4(htSNPs) in the HNF-4 region of region of chromosome 20q, which increase chromosome 20q, which increase susceptibility to Type 2 diabetes. susceptibility to Type 2 diabetes.

(1) Love-Gregory LD, (1) Love-Gregory LD, et al.et al. DiabetesDiabetes 2004;53:1134-40. 2004;53:1134-40.

(2) Silander K, (2) Silander K, et al.et al. DiabetesDiabetes 2004;53:1141-49. 2004;53:1141-49.

Collaborators in Investigations on the Collaborators in Investigations on the RW Pedigree (MODY1; HNF-4RW Pedigree (MODY1; HNF-4) ) [1/3][1/3]

1960s and 1970s:1960s and 1970s:John C Floyd, JrJohn C Floyd, Jr

Sumer B PekSumer B Pek

1973-1974 in clinical genetics:1973-1974 in clinical genetics:Robert B TattersallRobert B Tattersall

Collaborators in Investigations on the Collaborators in Investigations on the RW Pedigree (MODY1; HNF-4RW Pedigree (MODY1; HNF-4) ) [2/3][2/3]

1980s and 1990s in molecular genetics:1980s and 1990s in molecular genetics:M A Permutt (Washington U)M A Permutt (Washington U)

S C Elbein (U Utah)S C Elbein (U Utah)

G I Bell (U Chicago)G I Bell (U Chicago)

D W Bowden (Bowman Gray U)D W Bowden (Bowman Gray U)

M Stoffel (Rockefeller U)M Stoffel (Rockefeller U)

Collaborators in Investigations on the Collaborators in Investigations on the RW (MODY1, HNF-4RW (MODY1, HNF-4) & ) &

P (MODY3, HNF-1P (MODY3, HNF-1) Pedigrees) Pedigrees [3/3][3/3]

1990s in pathogenesis, 1990s in pathogenesis, insulin secretion/action, insulin secretion/action, etcetc::W H Herman (U Michigan)W H Herman (U Michigan)

J B Halter (U Michigan)J B Halter (U Michigan)

M J Smith (U Michigan)M J Smith (U Michigan)

L L Ilag (U MichiganL L Ilag (U Michigan

J Sturis (U Chicago)J Sturis (U Chicago)

M M Byrne (U Chicago)M M Byrne (U Chicago)

K S Polonsky (U Chicago)K S Polonsky (U Chicago)