- Created by: MazzaW
- Created on: 18-11-19 17:56
Type 1 Diabetes Mellitus
Autoimmune destruction of pancreatic beta cells.
Presents in preschoolers and teenagers. Does not present under 6 months old. Genetic risk- more likely to be passed on by fathers, HLA on chr 6 responsible for 50% genetic risk.
Sx: polydipsia, polyuria, wt loss, fatigue, DKA
Dx: clinical- usually have 1+ of hyperglycaemia, ketosis, rapid wt loss, PMH/FH of autoimmunity, BMI<25, age of onset <50, insulin dependent
Ix: C-peptide good marker of pre-hepatic insulin secretion (better discriminative value the longer it is done after Dx), islet Abs. If diagnostic uncertainty: GAD Ab, IA-2 Ab, ICA (islet cell autoAb)
Type 2 Diabetes Mellitus
RFs: FH, obesity, metabolic syndrome, sedentary lifestyle, Afro-Caribbean, Hx of gestational diabetes, PCOS, socioeconomic factors (higher risk in urban areas)
Peripheral insulin resistance + relative insulin deficiency (decreased beta cell function). Caused by fat accumulation in liver and pancreas.
Clinical Dx PLUS: random plasma glucose >11mmol/L OR fasting plasma glucose >7mmol/L OR HbA1c>48mmol/mol
If no Sx, need 2 confirmatory tests.
Don't use HbA1c if: young, acutely unwell, recently started drugs that may cause rapid changes in glucose, haemolytic anaemia, haemoglobinopathy, acute pancreatic damage, HIV, renal failure
Most common form of MODY in children, 30% of all UK MODY cases.
Pathophysiology: insulin secretion remains regulated but there is a higher threshold for glucose-stimulated insulin secretion. Microvascular complications not observed.
Presentation: incidental hyperglycaemia in children, common in gestational diabetes, residual insulin secretion at least 3 yrs after Dx of T1DM or lack of metabolic syndrome in those presumed to have T2DM
Clinical features: persistent raised fasting glucose, no extrapancreatic features, usually non-obese, often asymptomatic
Mgmt: do not use pharmacological intervention, stop any glucose-lowering treatment, consider testing parents/family to support Dx
Transcription factor MODY: HNF-1a and HNF-4a
HNF-1a MODY = most common form of MODY
Clinical picture: normoglycaemic in childhood, typically develop DM aged 12-30, worsening glycaemia with age, often misdiagnosed as T1DM, poor control does lead to complications
May have FH of DM.
Mgmt: v sensitive to low dose sulphonylureas so these are 1st line (gliclazide, glibenclamide), can also use prandial secretagogues. Stop insulin if it was previously prescribed after misdiagnosis as T1DM.
Transcription factor MODY: HNF-1b
HNF-1b is closely related to HNF-1a but causes a distinct DM phenotype with pancreatic and genitourinary anomalies. Causes 5-10% MODY in the UK.
Clinical features: RCAD (renal cysts and diabetes syndrome), renal function variable (can be mild, 50% require RRT), DM alone unusual
Mgmt: pts not sensitive to sulphonylureas, usually require insulin
Who is offered screening? BMI > 30, previous macrosomic baby (>4.5kg), previous GDM, FH of diabetes, from an ethnic minority known to be at higher risk
Screening test: OGTT
Criteria for Dx: fasting glucose >5.6 or plasma glucose (after 2hrs) > 7.8
Presentation: birth-6months, high glucose levels or DKA, low birth weight, very low C-peptide (low insulin release), DM may be transient or permanent, some subgroups have neurological involvement
Mechanism: 50% have mutation of K ATPase channel of beta cell, so no beta cell depolarisation and failure of insulin release
Mgmt: may respond to sulphonylurea therapy
Endocrinopathies causing diabetes
Cushing's syndrome: inhibition of insulin sensitivity (liver and muscle), stimulation of hepatic gluconeogenesis
Hyperthyroidism: increased hepatic gluconeogenesis, rapid GI glucose absorption
Acromegaly: stimulates gluconeogenesis and lipolysis, hepatic and muscle insulin resistance leading to hyperinsulinaemia
Phaeochromocytoma: inhibition of pancreatic insulin release, stimulation of hepatic gluconeogenesis
Glucagonoma: hepatic gluconeogenesis
Genetic syndromes linked to diabetes
Down's syndrome: autoimmunity (main factor)
DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness) AKA Wolfram's syndrome: AR inheritance of mutation in WFS1, reduced insulin production
Turner's syndrome: autoimmune T1DM
Prader Willi syndrome: obesity, insatiable craving for food
Lawrence-Moon and Bardet-Biedl syndromes: obesity, insulin resistance
Klinefelter's syndrome: high truncal fat, insulin resistance
Myotonic dystrophy: insulin resistance
Insulin resistance syndromes
Clinical features: persistent hyperglycaemia despite large doses of insulin, acanthosis nigricans, polycystic ovary syndrome
- insulin receptor defects (loss of function mutations): cause a range of resistance, includes Donahue syndrome and Rabsen-Mendenhall syndrome
- lipodystrophy syndromes
May be genetic or acquired. Classified by anatomical distribution of liposytrophy:
- congenital generalised LD: autosomal recessive, generalised absence of adipose tissue, increased appetite (absence of leptin), DM develops in 10-20yrs
- familial partial LD 1 (FPLD1): loss of limb fat, increased truncal fat, no identified gene to date
- FPLD2: loss of function mutation identified
- FPLD3: paucity of limb and gluteal fat, loss of function mutation in PPARg
Clinical features: partial or complete absence of adipose tissue, insulin resistance a feature of most, clinical expression more pronounced in women
Dx is clinically based.
Diabetes and HIV
Incidence of diabetes in HIV+ men treated with HAART is 4x greater than in HIV- men.
Pathophysiology: high levels of insulin, proinsulin and glucagon, insulin resistance may have an HIV component, protease inhibitors also implicated
Protease inhibitors and NRTIs: associated with increased risk of insulin resistance and diabetes, effects on glucose metabolism varied, indinavir blocks insulin-mediated glucose uptake by blockade of GLUT-4 and also increases hepatic glucose production