Dr. Ed. Barre Professor of Human Nutrition Concept of Glucose Regulation Dysregulation of glucose homeostasis-lecture 2 Dr. Ed. Barre Professor of Human Nutrition

Reading Focus on Dysregulation of Plasma Glucose Concentrations and the Ramifications of Such Dysregulation Chapter 19 (pages 476-487) Understanding Pathophysiology, First Canadian Edition. 2017. Elsevier Gestational diabetes Neonatal diabetes

Lecture 2-TOPICS Describe the aetiology and pathophysiology of gestational diabetes including relationships between gestational diabetes and metabolic syndrome Discuss the pathophysiological ramifications of gestational diabetes for mother and offspring Describe the aetiology and pathophysiology of neonatal diabetes mellitus (NDM) as well as the pathophysiological ramifications of NDM

Describe the aetiology and pathophysiology of gestational diabetes including relationships between gestational diabetes and metabolic syndrome

Gestational Diabetes Mellitus (GDM): Gestational Diabetes Mellitus (GDM) developing during some cases of pregnancy but usually disappears after pregnancy. Any degree of glucose intolerance and hence elevated plasma with onset or first recognition during pregnancy Typically in the 3rd trimester Pregnancy hormones are believed to interfere with insulin’s action on insulin receptors

Metabolic changes in pregnancy Aetiology Increased insulin resistance - may be due to excessive weight gain especially early in pregnancy Due to hormones secreted by the placenta that are “diabetogenic”: Growth hormone Human placental lactogen Progesterone Corticotropin releasing hormone

Gestational Diabetes This diagnosis is given when a woman, who has never had diabetes before, gets diabetes or has high blood sugar, when she is pregnant. Its medical name is gestational diabetes mellitus or GDM. It is one of the most common health problems for pregnant women. The word “gestational” actually refers to “during pregnancy.” PBRC 2009

Gestational Diabetes It occurs in about 5-7% of all pregnancies If not treated, gestational diabetes can cause health problems for the mother and the fetus. PBRC 2009

Pathophysiology of gestational diabetes including relationships between gestational diabetes and metabolic syndrome

GDM can be predicted by metabolic syndrome Metabolic syndrome can follow GDM GDM shares many features of T2D - elevated blood glucose (resistance to endogenous insulin action), dyslipidaemia, hypertension One feature that is not shared is between GDM and T2D is that GDM goes away after pregnancy (T2D does not go away- once one has T2D one has it for life or at least that this the current state of affairs).

Metabolic changes in pregnancy Transient maternal hyperglycemia occurs after meals because of increased insulin resistance

Describe the pathophysiological ramifications of gestational diabetes

Diabetes in Pregnancy: Clinical Implications Obstetric complications: Increased incidence of miscarriage Congenital malformations Incidence 4X higher than in general population Most significant remaining cause of fetal death is congenital malformation Association with hypertensive disorders of pregnancy Gestational hypertension Preeclampsia It has long been recognized that poorly controlled diabetes causes a multitude of obstetric complications

Diabetes in Pregnancy: Clinical implications Shoulder dystocia Fetal macrosomia

Diabetes in Pregnancy: Clinical Implications Obstetric complications (cont’d.): Preterm delivery Intrauterine fetal demise Traumatic delivery (e.g., shoulder dystocia) Operative vaginal delivery vacuum-assisted forceps-assisted

Diabetes in Pregnancy: Clinical Implications Fetal macrosomia Disproportionate amount of adipose tissue concentrated around shoulders and chest Respiratory distress syndrome Neonatal metabolic abnormalities: Hypoglycemia Hyperbilirubinemia/jaundice Organomegaly Polycythemia Perinatal mortality Long term predisposition to childhood obesity and metabolic syndrome-increased risk of type 2 diabetes in mother and child Other perinatal complications involve both long and short term exposure to high levels of serum glucose.

Describe the aetiology and pathophysiology of neonatal diabetes mellitus (NDM) as well as the pathological ramifications of NDM NDM is monogenic i.e. controlled by a single gene (however different genes can be involved so it not always the same gene that is involved)

TRANSIENT NEONATAL DIABETES Aetiology TNDM is caused by 6q24 alterations Heterozygous mutations in the KCNJ11 (11p15.1) and ABCC8 (11p15.1) genes account for 26% of cases. All of above- cause beta cell dysfunction

TRANSIENT NEONATAL DIABETES Pathophysiological ramifications Cardinal clinical manifestations include severe intrauterine growth retardation, hyperglycemia (within the first week of life beginning in the neonatal period and resolving usually by 18 months of age), and dehydration. The most commonly reported congenital abnormalities are macroglossia and umbilical hernia. A wide range of different associated clinical signs including, facial dysmorphism, deafness and neurological (as a rule no epilepsy), cardiac, metabolic, kidney or urinary tract anomalies are reported. Affected infants usually require insulin initially, but the need for insulin gradually declines with time. Developmental delay and learning difficulties may also be observed. Women who have had TNDM as infants are at risk for relapse during pregnancy. Ketoacidosis is generally absent (except in patients with KCNJ11 and ABCC8 mutations).

Pathophysiological ramifications of NDM (transient) Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For about 50% of patients, their diabetes will relapse in later life usually during adolescence or early adulthood.

PERMANENT NEONATAL DIABETES AETIOLOGY The incidence of NDM is estimated to be 1/95,000 to 1/150,000 live births. About 50% of NDM cases are permanent (PNDM) and 50% transient (TNDM). The condition has been reported in all ethnic groups and affects male and female infants equally. Mutations in 10 genes have been associated with PNDM: KCNJ11 (34% of cases), ABCC8 (24%), INS (13%), GCK (4%), PDX1 (<1%), GATA6, PTF1A, HNF1B, RFX6 and MNX1. These last five genes may be associated with syndromic forms. The genetic defects result in partial or complete insulin deficiency (i.e beta cell dysfunction), and for the last six in possible pancreatic hypoplasia. Diagnosis of PNDM is made in infants under 12 months of age with persistent hyperglycemia (plasma glucose concentration >150-200 mg/dl). Molecular genetic testing of the implicated genes confirms the diagnosis and guides management.

PERMANENT NEONATAL DIABETES Pathophysiology In KCNJ11 and ABCC8-related cases, patients usually present before three months of age with symptomatic hyperglycemia, and often ketoacidosis. Some patients present with marked hyperglycemia or diabetic ketoacidosis usually at nine weeks, but some at a much later age.

PERMANENT NEONATAL DIABETES Pathophysiological ramifications Initial clinical manifestations include hyperglycemia, glycosuria, intrauterine growth retardation, osmotic polyuria, severe dehydration, and failure to gain weight. The subsequent course of the disease depends on the genetic defect underlying DM. Most patients display some degree of developmental coordination disorder (including visual-spatial dyspraxia). Manifestations depend on the type of gene mutation involved.

PERMANENT NEONATAL DIABETES Pathophysiological ramifications GCK-related PNDM patients have permanent insulin-dependent diabetes from the first day of life and therefore similar pathophysiological ramifications. Homozygous PDX1 mutations or mutations in other genes such as GATA6, PTF1A or HNF1B are related to rare cases of pancreatic hypoplasia with severe insulin deficiency and possibly exocrine pancreatic insufficiency. Two groups can be distinguished based on pancreatic involvement: patients with abnormal pancreas development and children with a normal pancreas. Long-term complications include developmental delay, microalbuminuria, and retinopathy.

Pathophysiological ramifications of Permanent NDM Children with pathogenic variants in ABCC8 or KCNJ11 can be treated with oral sulfonylureas and therefore have pathophysiological ramifications similar to T2D; all others require long-term insulin therapy. High caloric intake is necessary for appropriate weight gain. Pancreatic enzyme replacement therapy is required for those with exocrine pancreatic insufficiency. Prevention of secondary complications: Aggressive treatment and frequent monitoring of blood glucose concentrations to avoid acute complications such as diabetic ketoacidosis and hypoglycemia and reduce the long-term complications of diabetes mellitus.

Summarising NDM https://www.niddk.nih.gov/health-information/diabetes/types/monogenic-neonatal-mellitus-mody

Summarising glucose dysregulation

Largely preventable! are: Metabolic syndrome Pre-diabetes Type 2 diabetes GDM All largely preventable by diet and exercise- cheap and easy ways to preserve your health, healthcare system, your jobs, your benefits, your retirement-it really is all about you. Don’t have time to eat and exercise well? Think about outcomes!!

Lecture 2-TOPICS Describe the aetiology and pathophysiology of gestational diabetes including relationships between gestational diabetes and metabolic syndrome Discuss the pathophysiological ramifications of gestational diabetes for mother and offspring Describe the aetiology and pathophysiology of neonatal diabetes mellitus (NDM) as well as the pathophysiological ramifications of NDM

Questions ?